key: cord-0997638-rnfn6opa
authors: Anton, Stephen D.; Cruz-Almeida, Yenisel; Singh, Arashdeep; Alpert, Jordan; Bensadon, Benjamin; Cabrera, Melanie; Clark, David J.; Ebner, Natalie; Esser, Karyn A.; Fillingim, Roger B.; Goicolea, Soamy Montesino; Han, Sung Min; Kallas, Henrique; Johnson, Alisa; Leeuwenburgh, Christiaan; Liu, Andrew C.; Manini, Todd M.; Marsiske, Michael; Moore, Frederick; Qiu, Peihua; Mankowski, Robert T.; Mardini, Mamoun; McLaren, Christian; Ranka, Sanjay; Rashidi, Parisa; Saini, Sunil; Sibille, Kimberly T.; Someya, Shinichi; Wohlgemuth, Stephanie; Tucker, Carolyn; Xiao, Rui; Pahor, Marco
title: Innovations in Geroscience to enhance mobility in older adults
date: 2020-10-22
journal: Exp Gerontol
DOI: 10.1016/j.exger.2020.111123
sha: 946c64cb7c7b1eb93b2d93a102168c8f43510046
doc_id: 997638
cord_uid: rnfn6opa

Aging is the primary risk factor for functional decline; thus, understanding and preventing disability among older adults has emerged as an important public health challenge of the 21st century. The science of gerontology – or geroscience - has the practical purpose of “adding life to the years.” The overall goal of geroscience is to increase healthspan, which refers to extending the portion of the lifespan in which the individual experiences enjoyment, satisfaction, and wellness. An important facet of this goal is preserving mobility, defined as the ability to move independently. Despite this clear purpose, this has proven to be a challenging endeavor as mobility and function in later life are influenced by a complex interaction of factors across multiple domains. Moreover, findings over the past decade have highlighted the complexity of walking and how targeting multiple systems, including the brain and sensory organs, as well as the environment in which a person lives, can have a dramatic effect on an older person's mobility and function. For these reasons, behavioral interventions that incorporate complex walking tasks and other activities of daily living appear to be especially helpful for improving mobility function. Other pharmaceutical interventions, such as oxytocin, and complementary and alternative interventions, such as massage therapy, may enhance physical function both through direct effects on biological mechanisms related to mobility, as well as indirectly through modulation of cognitive and socioemotional processes. Thus, the purpose of the present review is to describe evolving interventional approaches to enhance mobility and maintain healthspan in the growing population of older adults in the United States and countries throughout the world. Such interventions are likely to be greatly assisted by technological advances and the widespread adoption of virtual communications during and after the COVID-19 era.

Stephen D. Anton a (santon@ufl.edu), Yenisel Cruz-Almeida b (cryeni@ufl.edu), Arashdeep Singh c (a.singh@ufl.edu), Jordan Alpert d (Jordan.alpert@ufl.edu), Benjamin Bensadon a (bensadon@ufl.edu), Melanie Cabrera a (melanie.cabrera@ufl.edu), David 

While prolongation of life remains an important public health goal, of even greater significance is that extended life should involve preservation of the capacity to live independently and to function well [1] . The field of geroscience seeks to understand the genetic, molecular, and cellular mechanisms that make aging a major risk factor and driver of common chronic conditions and diseases of older people. Interventions targeting the fundamental biology of human aging have the potential to delay, if not prevent, the onset of aging-associated conditions [2] [3] [4] [5] [6] . The unprecedented growth of the aging population and increasing prevalence of chronic disease have underscored an urgent need for such interventions. If this the current trend in aging continues, the number of older persons (aged >60 years) will nearly triple in size globally, increasing from 673 million in 2005 to almost 2 billion by 2050 [7] .

Accordingly, the science of gerontologyor geroscience -has the practical purpose of understanding how aging processes enable diseases and to then apply this knowledge to reduce the emergence and progression of age-related diseases and disabilities. The ultimate goal is to develop feasible, practical, and safe interventions to delay the development of chronic diseases and conditions, while also increasing enjoyment, satisfaction, and quality of life, during the latter stages of an individual's lifespan. [8] Interventions that can achieve these objectives may also dramatically lower health care costs.

As we have previously described, [9, 10] a hallmark of successful aging is mobility, i.e. the ability to move without assistance, which is necessary for the maintenance of basic independent functioning [11, 12] . Additionally, mobility performance (i.e., walking speed) has emerged as a surrogate marker of overall health and functional ability among older adults. [13] Improvements in usual gait speed predict better survival and quality of life in older adults [14] .

In contrast, mobility limitation is associated with more rapid functional decline, reduced quality of life [15] , as well as hospitalization, nursing home placement, and increased mortality [16] [17] [18] [19] [20] (see Figure 1 ). For these reasons, understanding and preventing mobility disability among older adults has emerged as one of the most important public health opportunities of the 21 st century.

Therefore, identification of promising interventions to preserve mobility that can be widely implemented in older adults is a major clinical and public health priority [21] .

Since our previous review, [9] several advances in the field of geroscience have been achieved and are highlighted in this paper. For example, discoveries made in the past few years have illuminated the complex interactions between the brain and the body in affecting changes in mobility with aging. More specifically, the important role that the central and neuromuscular systems have in affecting mobility has spawned a host of new treatment options, such as use of neuro-modulatory adjuvants (e.g., transcranial direct stimulation) to enhance the beneficial effects of physical activity. In line with this, a growing body of research indicates that interventions designed to improve cognitive/emotional function (e.g., oxytocin) also have benefits effects on mobility and physical function. Thus, it appears virtually impossible to influence an individual's cognitive/emotional function without affecting their physical function, and vice-versa. An increased understanding of biopsychosocial factors that may contribute to functional decline can aid in the development of future interventions designed to improve mobility and function in at-risk older adults. Aided by technological developments, the range of interventions now available has greatly increased in the past five years. Thus, we have expanded our conceptual model to incorporate technology, neural factors, and environmental factors.

Although there is a strong consensus on this goal, there are challenges to developing such interventions as an older adult's mobility and functional level are affected by factors across J o u r n a l P r e -p r o o f Journal Pre-proof multiple domains. Moreover, the complex interactions between factors within biological, psychological, and social domains may increase the risk for functional decline and other agerelated chronic disease conditions. As such, promising interventions will need to take into account these multifaceted interactions and also recognize that affecting change in one domain can lead to changes in other domains. With this goal in mind, we first review the role of specific biological contributors to functional decline. Next, we describe key behavioral and psychosocial factors that can affect physical function and risk for functional decline in older adults. We then discuss promising interventions from clinical trials that can enhance physical function and mobility, as well as the role of smart and connected technologies in the delivery of these interventions (see Figure 2 ). In the final sections, we discuss the importance of preclinical models in guiding intervention selections, statistical considerations in aging research, as well as key strategies to effectively disseminate and implement efficacious interventions in clinical and community settings.

The rising prevalence of metabolic syndrome in older adults, a condition diagnosed based on the presence of three or more metabolic risk factors, including abdominal obesity, high triglycerides (TG), low HDL-cholesterol (HDL-C), high blood pressure (BP), and impaired glucose tolerance, correlates with sedentary lifestyles, and poor nutrition habits [22] [23] [24] [25] .

Approximately one-third of older adults in the USA are obese; however, nearly 55% of those aged 60 years or older are estimated to have metabolic syndrome [26] . Given the aging US population, the disproportionately high prevalence of the metabolic syndrome in older adults is a significant public health concern, as it substantially increases the risk for cardiovascular disease J o u r n a l P r e -p r o o f Journal Pre-proof (CVD) [27] [28] [29] [30] and is associated with increased all-cause mortality, disability, CVD mortality, myocardial infarction, and stroke [31] . Additionally, the metabolic syndrome is associated with impairments in basic activities of daily living, social activities, and lower extremity mobility [7, 32] .

Aging typically promotes a loss of fat-free mass which parallels to the reduction in metabolic rate and energy expenditure, particularly after the age of 50 [32] . This age-related muscle loss (i.e., sarcopenia) can diminish both the metabolic and mechanical functions of the skeletal muscle, [33, 34] a point of concern since skeletal muscle has the greatest contribution to an individual's metabolic rate [35] . In addition to the loss of total muscle mass, the muscle quality also declines with age due to increased fat infiltration within the muscle thus resulting in decreased muscle strength [36] and power [37] .

After the age of 50, it is noteworthy that adults lose muscle strength (i.e., dynapenia) at a much faster rate, approximately 3-4% year, than they lose muscle mass, approximately 1-2% per

year. Therefore, while muscle atrophy and weakness are certainly correlated, the former cannot fully explain lost muscle strength in late-life. Moreover, muscle weakness is a major independent contributor to maintaining physical independence in later life. [38] [39] [40] [41] [42] [43] 

It was originally thought that the loss of skeletal muscle mass largely explained the muscle weakness observed in older adults; however, more recent findings suggest that other anatomical and physiological factors also play an important role in muscle weakness. The mechanisms determining loss of muscle strength or power output are related to both neurological and skeletal muscle properties, as it is well known that the output from these sources control J o u r n a l P r e -p r o o f Journal Pre-proof muscle force and power production. Within the neuromuscular system, there are several potential mechanisms that may contribute to reductions in strength during aging, including reduced excitatory drive to the spinal motor neurons, reductions in motor neuron discharge rates, impairments in neuromuscular transmission, muscle cell death, muscle protein imbalance, reduced repair/regeneration of muscle cells and impairments in the excitation-contraction (E-C) coupling processes.

Aging in humans has been shown to be accompanied by robust reductions in the population of motor neurons and axon density [44] [45] [46] [47] . Between the ages of 60 and 70 there is a ~30% reduction in the number of functional motor units (motor units = motoneuron and innervated muscle fibers) [48] [49] [50] [51] and once the loss of motor units reaches a critical threshold, muscle strength begins to decline [52] . The exact underlying mechanisms of exhausted NMJ plasticity and motor neuron cell death remain obscure, but many factors such as deregulated inflammation, autophagy, reduced IGF-1 signaling, oxidative stress, and mitochondria dysfunction have been suggested to drive accelerated loss of muscle mass and function in late life [53, 54] .

Many factors contribute to a loss of automaticity of walking in older adults. One likely factor is impairment of the communication between the nervous system and muscle. Motor neurons innervate their axon terminals to the skeletal muscle fibers to form a neuromuscular junction (NMJ), which allows the presynaptic motor neurons to transmit chemical signals to the post-synaptic muscle fibers, leading to muscle contraction. During most of the adult life, there is considerable plasticity of the NMJ, where surviving motor units expand through collateral axonal sprouting to reinnervate any denervated NMJs [54] [55] [56] . Exhaustion of this plasticity (persistent denervation and failed reinnervation) accelerates muscle atrophy during aging and is associated with movement impairment and functional decline [44, 57] .

Accumulating evidence supports that models of cognitive brain aging may help us understand the decline in walking function in older adults [58] [59] [60] . Changes in brain structure and function may also contribute directly to loss of automaticity, as well as reduce the capacity for recruiting additional resources to compensate for the loss of automaticity [60, 61] . Additional research is needed to better understand the major modifiable neural factors that influence control of walking with older age, so that targeted interventions can be designed [58] .

Chronic pain conditions represent three of the five leading causes of disability in the US, including low back pain, which is the leading cause of disability both in the US and worldwide [62, 63] . While pain affects individuals throughout the lifespan, older adults are disproportionately impacted [64] . Another important contributor to mobility decline among older adults is movement-evoked pain (MEP). MEP refers to pain that is generated or exacerbated through physical movement or activity, and some evidence suggests that MEP may be driven by different mechanisms than pain at rest [65] . Recent findings in middle-aged and older adults with knee pain demonstrated a relationship between MEP and physical performance, highlighting the need to directly measure MEP when assessing functional performance in older adults [66] . Thus, one key mechanism through which pain may contribute to functional decline is through activity limitations among older adults [67] [68] [69] [70] [71] [72] [73] .

Emerging evidence also suggests that pain may affect aging processes. Indeed, several recent studies suggest that pain is associated with cellular aging. Specifically, a combination of high psychosocial stress and high levels of knee pain were associated with shorter telomeres among J o u r n a l P r e -p r o o f Journal Pre-proof middle-aged and older adults [74] , and subsequently these authors showed that more severe knee pain was associated with shorter telomeres [75] . More recently, chronic pain in older adults has been associated with brain aging [76] and a validated epigenetic measure of aging [77] . Thus, the relationship between pain and aging appears to be bidirectional and complex, impacting multiple body systems.

One area that is gaining recognition for the potential to impact aging processes is circadian rhythms, which are endogenously generated 24h cycles that can be observed in behavior, physiology and metabolic processes. Driven by the circadian clock, circadian rhythms are found in virtually every cell in the body [78] . Over the last ten years, research has uncovered that the circadian clock functions within cells to support daily tissue homeostasis, and disruption of the clocks leads to lowered resilience [79] . Studies in animal models support the decline in function of the circadian system with age, and this age-related decline appears to impact virtually all systems in the body including skeletal muscle and areas of the brain important for learning and memory [80] [81] [82] . In humans, studies have shown that circadian output changes with aging of muscle mass and strength [85] [86] [87] [88] [89] . Thus, the available evidence to date strongly implicates mitochondria as having a pivotal role in the pathogenesis of age-related functional decline, and it has been suggested that a substantial decrease in mitochondrial oxidative capacity in aging muscle might contribute to reduced exercise capacity in older adults [90] . Why there is a decrease in mitochondrial function with aging remains under debate, but emerging science indicates that there is a clear connection between mitochondrial biogenesis and function with fuel metabolism and circadian rhythms [91] .

Cardiovascular disease (CVD) is a leading cause of death among older adults in the United States and the prevalence increases proportionally with age. In particular, 70% of older adults between 60-79 years old and 85% of older adults 80 years and older suffer from CVD [92] . During aging, endothelial dysfunction induced by oxidative stress, inflammation and decline in bioavailability of nitric oxide (NO) leads to arterial stiffness, which overloads the heart leading to ventricular hypertrophy and myocardial fibrosis [93] . Endothelial dysfunction and the overloaded heart reduce arterial-ventricular coupling, reflecting impaired global cardiovascular performance [94] . Recent evidence has demonstrated that subclinical declines in cardiovascular function contribute to functional decline by impaired peripheral tissue perfusion [95] .

Although sepsis can affect all ages, it is recognized to be the "quintessential disease of the elderly" [96] . Studies have shown that both the incidence of sepsis and hospital mortality increases exponentially beyond the age of 65 years, with more than 1 million US Medicare recipients hospitalized each year with sepsis. Numerous age-related factors increase the risk for J o u r n a l P r e -p r o o f developing sepsis including comorbidities (e.g., chronic lung disease and renal insufficiency), malnutrition, increased aspiration risk from altered mental status and decreased gag/cough reflex and immobility. The diagnosis of sepsis is commonly delayed in older patients because of a blunted systemic inflammatory response syndrome (SIRS) and the presence of comorbidities that can cause confounding symptoms. As a result, older patients present as septic later in the process. They are more likely to progress into septic shock due to limited cardiac reserve and have worsening of existing organ dysfunctions.

The principal cause of sepsis is a dysregulated systemic immune response, which is negatively affected by aging. In contrast to younger adults, older patients have difficulty returning to immunity homeostasis, increasing their risk for sepsis recidivism. Pre-existing sarcopenia, frailty and cognitive disabilities all adversely affect recovery. Additionally, ongoing SIRS induces profound catabolism with tremendous loss of vital lean body mass despite early nutritional support intervention. Moreover, care for sepsis in the ICU often involves bedrest and mechanical ventilation, exacerbating the ongoing loss of muscle mass and function. Once SIRS has resolved, older sarcopenic sepsis survivors have anabolic resistance that makes them nonresponsive to nutritional and physical therapy interventions.

Our senses, hearing, vision, touch, smell, and taste play critical roles in survival throughout the course of life. Aging can affect all of these sensory systems, but the auditory system is thought to be especially vulnerable to age-related damages. Hearing loss is the third most prevalent chronic health condition affecting older adults and age-related hearing loss (AHL) is the most common form of hearing impairment [97] . The World Health Organization(WHO) estimates that one-third of persons over 65 years are affected by hearing J o u r n a l P r e -p r o o f loss [98] . Worldwide, approximately 466 million people suffer from hearing impairment and this number is expected to rise to 630 million by 2030 and over 900 million by 2050. AHL is characterized by poor speech understanding (especially in noisy situations), central auditory processing deficits, and social isolation [99] .

As humans age, both males and females undergo various changes in hormone levels, leading to numerous long term and significant internal changes. Although some of these changes may be more detrimental than others, common and problematic alterations include loss of muscle mass [100] , decreased bone mass [101] , and various cognitive impairments [102] , which all increase risk for mobility loss and loss of independence.

In men, aging is often associated with decreased testosterone [100] , which has been linked to bone loss [103] and decreased muscle mass [104] . With the loss of muscle and bone comes an increased risk of sarcopenia, oftentimes resulting in frailty, decreased functional mobility, and growing difficulties with independent living. In females, decreased estrogen levels post-menopause are often postulated to increase one's risk of sarcopenia and frailty [100] . Loss of estrogen is accompanied by an increase of pro-inflammatory cytokine IL-6, which downregulates insulin-like growth factor-1(IGF-1) [100] . High IL-6/low IGF-1 levels have been shown to significantly limit walking and mobility tasks of daily living [105] , increasing the risk for progressive disability in older females.

In addition to sex hormones, a decline in growth hormone (GH) has been observed with aging and is often associated with various changes in body composition, as well as physical and psychological functions [101] . As one approaches the fourth decade of life, there is a progressive decrease of GH secretion by ~15% each decade thereafter [101] . Age-related increases in body J o u r n a l P r e -p r o o f mass index (BMI) and diminished functional capacity tend to parallel the decline in GH secretion, although many other factors also likely contribute [101] .

In many cases, physical disability is directly caused or aggravated by acute events (stroke and hip fracture) and disease states (heart failure, coronary heart disease, diabetes, arthritis and peripheral artery disease) [106, 107] . However, a large and growing number of older adults experience progressive declines in physical function over several years culminating in agerelated physical disability with no clear connection to a single disease [108, 109] . Research over the past decade has highlighted the role of multiple body/biological/health systems in contributing to this decline. Moreover, many age-related conditions appear to affect other systems and may induce similar adverse changes at the cellular level.

Among the behavioral factors, low levels of physical activity combined with excessive and unhealthy calorie intake appear to strongly contribute to functional decline among older adults [110] . In line with this, a recent review of trends in US health by the U.S. Burden of Disease Collaborators found that high body mass index (BMI), smoking, and high fasting plasma glucose are the three most important risk factors for disease and disability in the United States [111] . Among these, only the prevalence of smoking is decreasing, while BMI and fasting plasma glucose levels are steadily increasing. skeletal muscle loses the ability to switch between metabolizing lipids and carbohydrates. In addition to the role caloric excess can have in promoting metabolic inflexibility, there is also increasing evidence that the "Western-type" diet that is high in sugar, fat, and processed foods seems to be associated with less ideal aging phenotypes [112] .

High levels of sedentary behavior (sitting) contributes to lipid accumulation [113] [114] [115] , metabolic impairments [116] , and loss of muscle mass during aging [117] , all of which strongly contribute to functional decline [118] [119] [120] [121] . These findings are of concern as the majority of middle-age Americans spend over half their waking day (~8-9 hours) engaged in sedentary pursuits [122, 123] , with older adults spending an even greater proportion (75%) of their waking hours engaged in sedentary behavior (~11 hours per day) [124] . Moreover, each additional hour of sedentary behavior was associated with increased risk of the metabolic syndrome, whereas every additional hour of light intensity activity was associated with reduced risk.

Perhaps the most common complaint older adults have is the lack of quality sleep. Sleep affects nearly every tissue and system in the body, from the brain, heart and muscle to metabolic, endocrine, cardiovascular and immune functions, as well as numerous cognitive processes such as learning and memory, emotion and motor control [125] . Similar to food and water, sleep is a basic human need, and sleep timing, duration, and quality are all essential to health. Despite this, sleep deficiency is prevalent in modern society, including an insufficient amount of sleep, low quality sleep, and sleep at the wrong time of day. According to a recent report from the Centers for Disease Control and Prevention (CDC), 30% of U.S. adults report some form of sleep deficiency [126, 127] .

Sleep deficiency is more prevalent in older adults, exhibiting common nighttime sleep abnormalities, such as early bedtime and rise time, sleep fragmentation (i.e. less consolidated sleep with frequent awakenings), short sleep duration, less total sleep, and deep sleep [128] ;

which is correlated with more frequent daytime naps. In fact, 1 in 4 older adults report severe daytime sleepiness that affects daytime mental and physical performance [129] . These agerelated sleep deficiencies have significant consequences for brain and body health, increasing the risk of chronic inflammatory and neuropsychiatric diseases, metabolic and cardiovascular disease, as well as mental health problems and even pain. For example, poor sleep quality and chronic pain are both tied to significant reductions in quality of life in aging [130] . Emerging evidence from our group suggests that sleep may negatively impact brain structure and function in older individuals, which may lead to worse self-reported pain [131, 132] .

An increased understanding of the behavioral factors that contribute to functional decline in otherwise healthy older adults can assist in both identifying at-risk older adults and designing targeted interventions for individuals in the later stages of life that maintain mobility and slow the rate of functional decline. It is recognized that there are many causes of functional decline and ultimately disability. While we believe behavioral factors, including over and undernutrition, physical inactivity, and sleep, have a central role in maintaining mobility in later life, the pathways leading to physical disability in older adults are likely complex and involve consideration of a larger number of etiologic factors.

Environment and social relationships can serve as either risk or protective factors for aging adults. Environmental factors across the lifespan interact with biology and contribute toward health outcomes [133] . Research shows that early life stressors can influence biological functioning, priming the stress system toward a level of heightened sensitivity increasing greater risk for later life health conditions and earlier mortality [134] . As individual age, environmental factors, life experiences, and personal and financial resources can buffer or exacerbate healthrelated conditions. Social relationships also influence health and well-being. Limitations in social relationships can be experienced as social isolation and loneliness [135] . Of concern, approximately one fourth of adults, individuals aged 65 years and older meet social isolation criteria and among individuals aged 60 years and older, greater than 40% endorse loneliness [135] .

Age-related life changes that increase susceptibility to social isolation and loneliness includes changes in health status limiting functioning and mobility; changes in family structure (divorce, childless); death of friends, family members, and spouse; auditory and visual changes reducing the ability to communicate and interact; and resource reductions including healthcare access and quality of care [135] . There is also research evidence that socially isolated older adults are less physically active independent of any mobility limitations [136] . However, whether or not declines in mobility mediate the well-established relationship between social isolation and all-cause mortality [137, 138] remains unclear.

Minority older adults are at an even greater risk to the health consequences of environmental and social factors. Higher frequency of negative environmental exposures, limited J o u r n a l P r e -p r o o f environmental resources, possible language limitations, and experiences of stigma and discrimination might be further contributing to increased risk of morbidity and mortality [133] .

Despite this increased risk for poor health outcomes, access to medical care is often limited and the extended wait times to receive care may discourage healthcare utilization, particularly preventive health services among minority populations [139] [140] [141] . Thus, environmental and social factors represent an area where research and evidence-based strategies can contribute to improved health outcomes [133, 142, 143] .

Older adults perceive mobility as essential to feeling whole and identify mobility assistance and adaptation as key to managing age-related changes [144] . In fact, older adults who met just one of five established frailty phenotype criteria were more likely to also be depressed, suggesting frailty has both physical and psychological components [145] . Also noteworthy, psychological factors such as balance efficacy and falls efficacy have previously been found to be more important than physical factors (e.g., fall history, medical morbidity, and balance tests) in predicting future falls [146] .

Theoretically, self-efficacy for specific tasks, mood, and behavior have a reciprocal influence on an older person's decision making and performance. For example, lower baseline self-efficacy for functional tasks predicted decreased walking performance and stair ascent among older women with osteoarthritis [147] . Falls efficacy, a measure of falls-specific selfefficacy, can be independently predicted by normal walking pace, anxiety, and depression [148] .

Dizziness, another common mobility-related complaint of older adults, has been associated with lower falls efficacy and slower walking speed [149] . These trends are consistent with other data J o u r n a l P r e -p r o o f showing fall history and female gender independently predict fear of falling [150] and mobility device use [151] .

Consistent with the data on the importance of psychosocial factors in mobility, a number of mobility-related clinical interventions are integrating falls-specific self-efficacy [152 2017 ], balance-specific [153] and other psychological concepts into trials targeting frailty in older adults [154] . Further, these trials are also targeting motivation for physical activity [155] , adherence to exercise programs [156] , fall prevention [157] , and interventions to reduce the fear of falling and improve balance such as yoga [158] . Protocols are emphasizing the need to tailor to older adult's preferences, personal choice, and providing social support [159] . These factors should align with older adults' own attitudes and perceived needs [160] , as well as older adults' perceived enablers and barriers to participation in strength and balance activities (barriers = risk of cardiac events, death, and hyper muscularity; enablers = potential improvement in the ability to complete daily activities, prevent deterioration /disability, and decreased risk and fear of falling) [161] . In a 6month integrated care program that included problem-solving psychotherapy reported improvements in frailty were sustained at one year follow up [162] . Although these studies suggest promising results, the integrated biopsychosocial approach to mobility is still underutilized.

Poor Nutrition may be a key factor that promotes metabolic syndrome and can exacerbate a decline in physical function and mobility. Given the link between metabolic syndrome or obesity with the musculoskeletal decline among the older population, it is no surprise that dietary interventions that reduce bodyweight also improve health outcomes in older adults. Dietary J o u r n a l P r e -p r o o f restriction (or caloric restriction), defined as a mild reduction of energy intake without malnutrition, delays aging in nearly all animal species tested so far [163] . In addition to promoting longevity in various model organisms (e.g., yeast, worm, fly, mouse) [163, 164] , dietary restriction had also been shown to be beneficial for enhancing physical function and mobility in older adults [254] [255] [256] [257] . Furthermore, in overweight humans, caloric restriction has been shown to reduce several cardiac risk factors [165] [166] [167] , improving insulin-sensitivity [168] , and enhancing mitochondrial function [169] .

Current Challenges: Despite health-promoting biological changes, there are two important concerns related to calorie restriction interventions in older adults. First, weight loss could accelerate aging-associated muscle loss and thereby have adverse effects on physical function [170, 171] . Second, most individuals have difficulty engaging in caloric restriction over the long-term and frequently regain weight that was lost [172] . For these reasons, alternative innovative dietary approaches for reducing body weight, specifically body fat, in overweight, older adults at risk for the functional decline are currently being explored.

Innovations from Geroscience: One alternative dietary approach that has been suggested to produce similar biological changes as calorie restriction that has received increasing interest from the scientific community is Intermittent Fasting or Time-Restricted Eating (TRE) [173] . In contrast to traditional calorie restriction paradigms, there is typically no restriction to calorie consumption in TRE during designated eating periods (typically 8 -12 hours). In a recent review of the effects of intermittent fasting regimens, specifically TRE and alternate-day fasting, we found that TRE produced significant reductions in body fat without significant loss of lean tissue, suggesting it may be an effective intervention approach for overweight, older adults [173] .

Another area of increasing scientific interest is understanding the role of dietary composition in impacting human physiology and physical performance. For example, the Mediterranean diet, which consists of healthy fats, fiber, fish, and minimally processed, plantbased foods, has been shown to provide health benefits including improving cardiovascular function, glucose control and decreasing body weight among older adults [174] [175] [176] . Also, noteworthy, in some preclinical studies conducted in rodent models, the ketogenic diet has been shown to extend longevity and healthspan, [270[177] improve memory and cognition, [177] [178] [179] and improve endurance athletic performance [274, 275] . Based on such findings, the lowcarbohydrate, high-fat ketogenic diet has attracted increasing attention as a potential dietary intervention to promote healthy aging.

Future Directions: To date, the impact of diet interventions on physical function and mobility among seniors with aging-associated morbidities is unknown. Although some risk may be associated with lifestyle-based weight loss interventions in older adults, obesity, and sedentary lifestyle are known to predict the development of disability in otherwise healthy older adults [119, 180] . However, randomized controlled studies are needed to demonstrate whether the benefits of these interventions outweigh the risks before implementing these interventions on a broad scale. An important primary focus of these interventions should be enhancing and/or maintaining fat-free mass, as high-quality muscle is the primary driver of metabolism and also directly impacts mobility and physical function [14, 181] . Notably, as multimorbidity is often a characteristic feature observed in older individuals with impairments in mobility, a Geroscience Approach will be instrumental in determining the long-term efficacy of nutrition-based interventions and addressing the potential challenges with aging-associated comorbidities.

Exercise provides benefits to all major body systems, including the nervous system. Aerobic exercise, in particular, can enhance brain health by upregulating neurotrophic factors that improve nerve structure and function [182] . To prevent functional decline, the American College of Sports Medicine (ACSM) guidelines for older adults recommend a regular exercise program that includes a combination of endurance and resistance training [183] . In support of these recommendations, low-intensity aerobic activity such as walking 4-7 days per week [184] or going up and down a 10-stair staircase [185] , have been shown to be protective against loss of mobility and functional decline [184] [185] [186] .

Current Challenges: While structured physical activity is a powerful tool to improve overall health in older adults, involvement in structured physical activity may be overwhelming for frail older adults who are home-bound and have poor physical performance. Older adults may not be capable of participating in structured, institution-based physical activity programs with multiple visits to research sites due to poor health status and distant living locations.

Innovations from Geroscience. Our group has shown that a structured, moderate-intensity physical activity program compared with a health education program reduced the incidence of major mobility disability over 2.6 years among older adults at risk for disability [187] . Other studies have found that resistance training can reduce and delay age-related changes in functional mobility [188] , improves leg strength [189] , and prevents falls by improving transfer of weight and swooping motions in the elderly [190] . 

Reduction of sedentary behavior may be an alternative way to deliver a home-based and remotely supervised intervention to improve the functional status in older adults who cannot engage in center-based physical activity programs. For example, an intervention to reduce sedentary time over 12-weeks improved scores on the short physical performance battery (SPPB) and self-reported moderate-to-vigorous physical activity (MVPA) levels in older men and women [192] . Such it could be a promising intervention to improve physical function in frail older adults in a home-based setting. Strong positive associations between breaks in sedentary time with physical function in older adults have also recently been reported [193] .

Challenges: Remotely delivered interventions are more difficult to achieve long-term adherence to the intervention tasks. Additionally, considering heterogenous levels of daily activity and sedentary time among individuals, it is challenging to set daily frequency of sedentary time reduction breaks and design the methods for prompting these breaks as well as an amount of steps to be reached daily. [194] Innovations from Geroscience: Thanks to new developments of well-accepted wearable technology in older adults [195] , such as the Fitbit Alta device, activity and sedentary-behavior levels can be monitored and registered remotely, and importantly, users can be reminded automatically to transition from sitting to standing position and perform brief light-intensity activity such as leisurely walking [196] . For example, participants using wearable technology aimed to achieve a minimum goal of 25% increase in daily posture breaks, and an additional 1,000 steps a day to baseline, which is considered clinically meaningful in a geriatric rehabilitation population [197] . This novel and practical approach, is less physically strenuous, J o u r n a l P r e -p r o o f does not require frequent visits to research sites, and can be operated and monitored remotely by a research team.

Future Directions: Future randomized clinical trials are needed to test wearable technologies in a population of frail older adults with poor physical function, multi-morbidities, and live a far distance from research facilities.

Given the importance of physical activity and exercise for healthy aging, it is important to consider how these can be optimized to promote neural control of walking. The mode of activity/exercise may be important, and there may be adjuvant interventions that promote neural plasticity.

Innovations from Geroscience. Task-specific aerobic exercise that incorporates complex walking tasks and other activities of daily living may be especially helpful for mobility function [198] . An example of these interventions is the use of non-invasive neuromodulation such as transcranial direct current stimulation (tDCS), a mild form of electrical stimulation that is safely delivered via electrode sponges placed on the scalp. tDCS does not directly activate brain neurons, but rather alters the neuronal membrane potential, which is believed to alter the likelihood of eliciting neuron activity (either increased or decreased likelihood, depending on the stimulation parameters) [199] . When paired with task practice, excitatory tDCS might reinforce task-specific neural circuits, enhance learning, retention of new skills, and has been shown to benefit walking tasks in preliminary studies [200] [201] [202] [203] . 

Cognitive interventions refer to a broad set of methods designed to improve or maintain cognitive functioning [204] . Because many forms of cognition (e.g., memory, reasoning, speed, executive functioning, attention, working memory) are change with age, and are associated with functional losses in later adulthood [204] [205] [206] , the field of cognitive intervention research has been rather broad. Methods of intervention have varied from cognitive training (e.g., providing elders with strategic instruction and practice/feedback in age-vulnerable cognitive domains i ), engagement [207] (having elders engage in complex real-world or leisure activities, including video games) [208] , quilting and digital photography [209] , performing arts [210, 211] interacting with technology [211, 212] , to a wide variety of physical and nutritional strategies (e.g., cardiovascular and strength training, anti-inflammatory diets [213] ). Most of this research has sought to investigate whether interventions can improve cognition and/or cognitively demanding activities of daily living.

Innovations from Geroscience. Useful field of view training progressively and adaptively trains older individuals to improve the speed with which they make accurate perceptual judgments about targets presented in the center of the field of view, while also correctly noting the location of peripheral objects presented on a display [214] . Restrictions in useful field of view have been associated with problems of mobility [215] , balance [216] and increased risk of falling [217] , although direct training benefits have not yet been widely reported. Of relevance to the mobility domain, older drivers who received useful field of view training showed a roughly 50% reduction in five-year motor vehicle crash rates [218] , presumably because of the improved ability to rapidly monitor a broad visual display and to divide attention between central and J o u r n a l P r e -p r o o f peripheral targets. The unifying feature of each of these domains of successful cognitive training is the focus on divided attention. In all cases, training included the feature of exposing elders to two tasks at once with one task usually representing a balance/gait or visual-perceptual challenge. Generalization of training to mobility tasks seems to be associated with the improved ability to attend to multiple tasks at once, or perhaps to be resistant to distracting tasks by having greater control over attentional prioritization (i.e., reducing the effects of distraction, or improving the ability to exert controlled attentional processing over mobility-relevant tasks).

The question of whether cognitive interventions might also improve mobility and physical functioning has received less attention, but a few areas of inquiry have yielded supportive findings. First, dual-task training has been shown to improve standing balance, gait, and to reduce fall risk [213, [219] [220] [221] . The rationale for such studies is that balance and gait are thought to be under central (executive) control, and improving attentional capacity to concurrently conduct cognitive and motor challenges will improve the ability to maintain adequate mobility under distracting conditions, as distractions are thought to put elders at a high risk for falls.

There are a number of hormonal interventions that have the potential to impact mobility and improve physical function. We focus on one promising compound, the neuropeptide oxytocin, which serves various adaptive and interrelated physiological, behavioral, and cognitive functions [222] . As a hormone, oxytocin is released into the peripheral circulation and acts directly on multiple organ systems. For example, in humans, low plasma oxytocin levels were associated with increased prevalence of chronic pain, and acute (i.e., one-time) intranasal oxytocin administration decreased experimental pain sensitivity, increased pain inhibition, and J o u r n a l P r e -p r o o f Journal Pre-proof improved mood and positive affect. In addition, there is increasing evidence of improved wound healing and anti-inflammatory effects associated with oxytocin [223] , promoting physical health.

Innovations from Geroscience: The ability to administer oxytocin centrally via nasal spray [224, 225] , with minimal and inconsistent side effects [226] , has spurred research to explore the neuropeptide's therapeutic potential across functional domains, including physical health and in aging [227] [228] [229] [230] . Going beyond its classic role in labor and lactation [231] , oxytocin has been demonstrated to modulate higher-order cognitive processing [232] , improve vasculature in the cardiovascular system, benefits weight control, and insulin sensitivity [222, 233] . Oxytocin has also been shown to play a crucial role in endogenous analgesia and has recently been discussed as a promising treatment for pain in older individuals [234] . These analgesic mechanisms may be explained by oxytocin's role as both a neurotransmitter and a paracrine hormone and may be associated with brain-morphological processes. As a neurotransmitter, oxytocin may provide analgesia via widespread effects on the brain and spinal cord.

In humans, emerging evidence supports an association between plasma oxytocin levels and brain volumes [235, 236] . Preliminary data from a 4-week intranasal oxytocin intervention in older men found increased regional gray matter volume following oxytocin but not placebo treatment, with this oxytocin-induced enlargement in brain volume was associated with improved processing speed [237] . Furthermore, animal models that administer repeated oxytocin treatment have documented brain changes driven by cell proliferation, differentiation, and dendritic complexity of new-born neurons in the hippocampus [238] . Findings in both models offer promise for future investigations into the potential of intranasal delivery of oxytocin to counteract cognitive decline and positively affect physical health in aging. Additionally, data J o u r n a l P r e -p r o o f from an animal model that systematically administered oxytocin found that the administration enhanced muscle regeneration after injury through activation of stem cells and MAPK/ERK signaling [239] .

Future Directions: Only one study to date has specifically examined the effects of intranasal oxytocin administration on physical health among older adults and found that 10-days of oxytocin spray was associated with less self-reported physical decline and reduced selfreported fatigue [240] . The promising findings from these diverse emerging fields call for more systematic research on both acute and chronic oxytocin intervention towards physical function among older adults. Examination of exogenous oxytocin's direct and mediated effects, and interaction with the endogenous oxytocin system (e.g., naturally circulating neuropeptide levels, oxytocin receptor gene polymorphisms and methylation levels [228, 241] ), forms an interesting angle for future research on interventions promoting physical function and mobility in aging.

In addition, there is growing support in the literature of sex dimorphism in the oxytocin system [226] , including in aging [241] , and evidence of sex-dimorphic effects of intranasally administered oxytocin on both brain [222, 228] and behavior [50, 222, 228] , including among older adults. In an age-heterogenous sample of generally healthy women and men, plasma oxytocin levels were higher in women than men, with young women showing the numerically highest levels and older men showing the numerically lowest plasma oxytocin levels [241] .

Based on this emerging evidence, future research on the application of oxytocin's effects across different functional domains during aging will benefit from consideratin of sex-by-age variations.

Pharmacological interventions targeted at underlying mechanisms of mobility decline may also lead to improvements in mobility and physical function in older adults. For example, cell senescence characterized by a loss of cell proliferative capacity, increased metabolic activity, and resistance to apoptosis is a major contributing factor to the development of various agerelated conditions. Thus, targeting the removal of senescent cells or suppressing the senescenceassociated secretory phenotype may be helpful in improving physical function [242] .

Specifically, inhibition of cytoplasmic Hsp90 (a chaperone protein needed for proper protein folding) induced by Hsp90 inhibitors causes senescent cells to be more susceptible to apoptosis.

Other pharmacological agents aimed to help proper protein folding or remove misfolded protein aggregates may also delay the onset of age-related diseases and subsequently prevent or ameliorate physical functional decline from these sources.

The idea that aging itself may be modified through a pharmaceutical intervention will be tested in the Targeting Aging with Metformin (TAME) proposal, the first clinical trial to examine an intervention to slow aging rather than to treat a specific age-related chronic disease in humans pharmacologically [243] . The impetus for this trial is that metformin has been demonstrated to have protective effects against several agerelated diseases in humans. However, there does not appear to be a single biological mechanism targeted. Rather metformin appears to have broad systemic effects, which can enhance insulin sensitivity and upregulate stress responses at the cellular level.

Further, targeting cognition pharmacologically to improve mobility or prevent further decline may be possible, given the brain's neurotransmitter systems shared between cognitive function and the circuits controlling gait. Specifically, drugs targeting the cholinergic, J o u r n a l P r e -p r o o f dopaminergic and glutamatergic systems have been reported with various degrees of success in individuals with Alzheimer's and Parkinson's Disease [244] , but may be an additional option to explore in cognitively intact older adults with poor mobility.

Future Directions: To date, there is very limited research focused on pharmacologically targeting aging for improving physical function. Given the mosaic of aging processes and potential multi-factorial underlying mechanisms, a Geroscience approach will be needed to test interventions with multi-functional properties that target the biopsychosocial contributors to aging processes.

Natural compounds may also represent an important source of potential new interventions for older individuals. Similar to pharmaceutical agents, these compounds would likely be most effectively used as an adjunct treatment with lifestyle interventions, behavioral self-management programs, physical exercise, or cognitive interventions.

Current Challenges: For the vast majority of these compounds, the findings have primarily been shown in preclinical models and have not yet been translated to humans, and/or few clinical trials have shown positive effects on mobility in older adults when biologically based approaches are used alone and not in combination with a behavioral intervention [245] .

Innovations from Geroscience: Studies to date suggest some natural compounds may be effective adjuvants to lifestyle interventions. In this section, we will focus on one promising nutraceutical compound, nicotinamide riboside (NR), a form of vitamin B3 that stabilizes the NAD metabolome (NAD+, NADH, NADP+ and NADPH), which in a homeostatic state, mediates transformations from food into energy and repair processes [246, 247] . Given the NAD metabolome destabilizes with age [248] , supplementation with NR has been shown to stabilize J o u r n a l P r e -p r o o f the NAD metabolome in a variety of tissues [249] . Clinical studies have demonstrated excellent tolerabilty and safety of NR supplementation in middle-aged and older adults, and improved vascular function [250] and reduced fat tissue [251] following 6 weeks of supplementation.

Future Directions: The effects of NR supplementation alone on physical performance in older humans are unclear, and therefore future studies warrant investigations of longer-duration NR supplementation on physical performance, weight loss and cardiovascular function in humans [252, 253] . Much will be learned about the promise of preclinical findings to translate to humans, as well as their compatibility with other interventions, in the coming years.

There are many promising complementary and alternative treatment modalities, including biofeedback, hypnosis, meditation, mindful exercise, massage and other types of body-work, acupuncture, and music therapy, that have the potential to improve mobility and physical function in older adults. Here we will focus on the potential role of massage therapy (MT), which is a mind-body intervention that has been shown to improve muscle function and quality, preserve of neuromuscular function, improve sleep quality and psychological functioning [229, [254] [255] [256] [257] [258] ; [259] ; [260] . Additionally, a growing body of literature supports the use of MT to treat chronic musculoskeletal pain associated with aging [261] [262] [263] [264] .

Current Challenges: While MT shows significant promise for improving factors associated with physical function and quality of life, there are important considerations for older adults, including access, attitudes, and approach. Attitudes towards complementary health approaches, specifically MT, are often biased towards a luxury service instead of an actual medical intervention. Also declines in mobility and independence may inhibit treatment seeking.

Innovations from Geroscience: Specific to biological processes in aging, MT has been shown to modify gene expression, protein synthesis, and inflammatory responses [254] [255] [256] [257] , as well as improve peak isometric torque recovery following intense exercise [265] , and protect against loss of strength and fibrotic nerve and connective tissue changes associated with repetitive motion injuries [266] . Massage therapy has also been demonstrated to modulate inflammatory processes that may be protective in aging [267, 268] . Of particular relevance, recent preclinical studies using rodent models, demonstrated MT induced immunomodulatory changes (e.g., increased satellite cell number) comparable to those seen in younger animals without damaging muscle tissues. [269] The beneficial effects of massage therapy appear to take place quickly, as a single 10-minute massage therapy session following exercise-induced muscle damage was found to be beneficial for reducing inflammation and promoting mitochondrial biogenesis [270] . Additionally, massage therapy is capable of altering proprioceptive feedback to the central nervous system [271, 272] , a critical component for maintaining mobility in aging.

adults have yet to be fully elucidated, it is likely that massage therapy can serve a vital role in helping older adults maintain mobility by reducing pain, improving muscle functioning, maintaining proprioceptive abilities, and altering negative inflammatory processes, while improving psychological functioning [259, 260, [273] [274] [275] . Although MT may need to be modified to accommodate older adults' needs, it appears to be a safe and effective intervention.

Given that MT acts upon multiple important pathways for mobility and independence, applying an integrated Geroscience approach will improve our understanding of MT in addressing agerelated mobility and functional declines.

There is now evidence to support a wide variety of intervention approaches to improve mobility and attenuate functional decline in older adults. Both behavioral and biological interventions hold great promise for improving function and mobility and thereby extending healthspan and promoting wellness in functionally limited but healthy older adults. As noted previously, such interventions may enhance physical function directly, as well as indirectly through modulation of cognitive and socioemotional processes. These processes include depression, social stress, and anxiety, which all have high relevance in aging and may contribute to social isolation and reduced well-being among older adults.

The utility of such interventions to produce desired outcomes is directly impacted by participant adherence to prescribed treatments, and even the most efficacious intervention can be ineffective if the patient fails to follow treatment recommendations. Thus, it is very important to carefully evaluate the sustainability of such interventions, especially in light of research demonstrating that individuals who are not fully adherent to health interventions experience significantly fewer health benefits [276] . A variety of factors can affect long-term adherence to health promotion behaviors, including the complexity of the required changes, the number of decision points needed to carry out such changes on a daily basis, and a number of environmental, socio-cultural, and psychological influences [276] . This suggests the need for two approaches to enhance the effectiveness of behavioral and biologically-based interventions: 1) continued refinement of strategies that can enhance the delivery of and adherence to such interventions, and 2) development of novel intervention approaches (e.g., intermittent fasting and intermittent activity bouts) that have the potential to produce similar health benefits as traditional lifestyle approaches and also may be easier to sustain over the long-term.

The role that technological advances may have in increasing the effectiveness of both traditional interventions, as well as more novel intervention approaches, is a topic of great interest. In the section below, we describe some of the key considerations in delivering digital and mobile health (mHealth) based interventions in older adults.

Personally-held devices, such as smartphones, smartwatches and fitness trackers, provide a ubiquitous infrastructure for researchers and clinicians to passively collect a moment-bymoment quantification of individuals' behavior in their own environment, or recently referred to as digital phenotyping.

Smartphones are considered the most common electronically held devices. Pew Research Center (PRC) conducted a survey about the ownership of smartphones in 2019 showing that 81% of Americans and 53% of older adults own smartphones, usage doubling among Americans and nearly quadrupling among older adults since 2010 [277, 278] . Smartwatches are also growing rapidly. The International Data Corporation (IDC) Worldwide Quarterly Wearable Device Tracker published that smartwatches accounted for 44.2% of the wearable market in 2018 and is expected to rise to 47.1% by 2023 [279] . PRC has published recently a survey showing that onein-five Americans (21%) wear a smartwatch or a fitness tracker [280] . A recent study by Manini and colleagues [281] about the perception of older adults (65+ years) towards the use of smartwatch technology for assessing pain showed an overall positive view.

Data collected using smart devices fall under two main categories: active and passive data. The essential difference between these two types is the involvement of participants in reporting data. The active data is described as questions or surveys that a participant has to self-J o u r n a l P r e -p r o o f report at specific times. This data is commonly used for ecological momentary assessment (e.g., pain, mood, or fatigue).

In contrast, passive data collection does not require participants to report any data.

Participants are only required to carry the smart device to be able to continuously collect data through built-in sensors. The type of passively collected data and the quality depend on the availability and modalities of sensors. The most common sensors available are: 1) global positioning sensor (GPS) that could be used to measure life-space mobility; which is a measure of the spatial size and frequency of interaction with the surrounding environment; 2) accelerometer that could be used to track physical activity pattern and energy expenditure; 3) microphone that could be used to collect voice samples to be used to extract vocal markers that can serve as a prognostic value for neurological disorders; and 4) call and text logs that can convey information about the size and reciprocity of a person's social network and can also serve as a prognostic value for neurological and psychological disorders.

The huge amount of data collected from personally held devices contain hidden, but useful knowledge about the behavior of an individual. Fortunately, the advancement of machine learning techniques allowed us to tap into this data and extract patterns.

In recent years, sensors embedded into wearable and personal devices such as smartphones have made it possible to develop many mHealth apps, e.g. for tracking physical activity, monitoring blood pressure and heart rate, medication reminders, and many more [282, 283] . Some mHealth apps additionally provide Just in Time (JIT) interventions (Figure 4) , such as prompting physical activity based on inferred levels of activity or daily steps.

A number of recent studies have utilized such mHealth tools in controlled trials to examine mHealth interventions, especially for chronic disease management [284] . Several studies have used mHealth intervention tools in cardiovascular and diabetes patients, including the pilot mobile Atrial Fibrillation (mAF) [285] Trial (n = 113, cluster randomized design pilot study). As the first mHealth trial of atrial fibrillation patients, mAF showed improved drug adherence and anticoagulant satisfaction versus the usual care. In a larger study, the Heart Failure II (TIM-HF2) trial [286] (n = 1571, randomized parallel-groups), utilized remote monitoring and demonstrated that it could reduce the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality. In a remote monitoring study, Giacomelli et al. [287] showed that remote monitoring after hospitalization for heart failure in older adults had no impact on the primary end-point but it significantly improved patients' quality of life.

Physical activity promotion also has been examined in several mHealth trials, including the mActive [288] trial which showed that tracking and texting intervention increased physical activity. Amorim and colleagues [289] carried out a randomized controlled trial by integrating mHealth, health coaching, and physical activity for patients sufferings from chronic low back pain, demonstrating feasibility and acceptance and a reduction in care-seeking after treatment discharge. Other studies have examined mHealth interventions for promoting mental health in clinical trials, including using smartphone cognitive behavioral therapy for refractory depression [290] and smartphone-delivered intervention in patients with a serious and persistent mental health condition, with the improvement shown among patients from racial minority groups [291] .

These recent intervention studies and especially controlled trials show promise for the potential scalability and acceptance of mHealth tools. An important but sometimes overlooked J o u r n a l P r e -p r o o f aspect of developing mHealth intervention tools is conducting formative usability evaluation research, besides evaluating efficacy in formal trials. Tools must be designed to effectively communicate the proper information by being interactive, interoperable, engaging, and accessible for diverse audiences [292, 293] . Therefore, the following attributes should be considered during the development, adoption, and implementation of mHealth tools: 1) ease of use; 2) how the tool fits within the policies, practices, and technical infrastructure of existing health and social systems; and 3) whether intended users can understand and apply the health information provided. Performing needs analysis and audience analysis can help guide the design to achieve such objectives [293] .

In summary, while mHealth tools may enhance the delivery of some interventions, especially in chronic disease management, evidence regarding their effectiveness for geriatric conditions is still mixed [284, 294] . Additionally, most controlled trials have been carried out in high-income countries, and evidence on the effectiveness of such tools in lower-income countries is missing [284] . Finally, there is a lack of end-to-end systems for sharing JIT intervention results with providers through existing Electronic Health Record (EHR) systems.

Both humans and animals exhibit an age-dependent progressive decline in mobility [295] [296] [297] [298] . Thus, mechanistic studies of age-related mobility impairment in pre-clinical models could advance our understanding of the fundamental mechanisms underlying disability. For example, there is much that can be learned from the study of the simple organism C. elegans. Despite its simple anatomy, C. elegans is capable of multifaceted behaviors in response to diverse environmental and intrinsic cues, and exhibits an age-associated decline in locomotion [296, 299] . The multitude of genetic tools available also makes C. elegans an invaluable model system for the study of cellular and molecular mechanisms underlying aging-related locomotor and J o u r n a l P r e -p r o o f movement decline [300] . In C. elegans, the progressive deterioration of muscle occurs with age, which resembles human sarcopenia [301] . Importantly, the functional decline of motor neurons at the neural muscular junctions precedes the deterioration of muscle tissues during C. elegans aging [302] , indicating an important role of motor neurons in the age-related mobility impairment.

Findings from pre-clinical models have led to the identification of important biological mechanisms related to the aging process including mitochondrial function and dynamics [303, 304] , autophagy [305, 306] , oxidative stress [307] , chronic inflammation [308] , muscle composition [309] , hormonal factors [310] , and neurodegeneration [311] . Moreover, preclinical studies have led to the transformative discovery that interventions targeting the fundamental biology of human aging have the potential to delay, if not prevent, the onset of aging-associated conditions [2] [3] [4] [5] [6] . Ultimately a strong translational geroscience approach is needed to understand the disease-mediated pathways associated with functional decline and identify promising interventions to maintain mobility and physical function (see Figure 4 ).

As aging research becomes more information-based, statistics plays a critical role in almost all research topics discussed in the previous sections. For any given aging research project, statistical support is needed at almost all stages starting with the formulation of a scientific hypothesis, study design, data collection, data management and analysis, and conclusion making and ending with manuscript writing. Often, the earlier a statistician is involved in an aging research project, the more productive the project will become.

Let us use a specific example to demonstrate how statistics can significantly help aging research. Assume that a research project aims to investigate whether an intervention (e.g., a J o u r n a l P r e -p r o o f nutritional supplement) can improve older adults' mobility. To make the hypothesis more specific, we first need to determine major mobility measurements. According to Webber [312] , mobility can be measured in five dimensions (i.e., cognitive, psychosocial, physical, environmental, and financial), and there are many different ways to measure mobility in each dimension. If we are interested in all five dimensions and would like to develop a single mobility index or choose some important ones from all possible mobility measures, then some preliminary studies to collect data on these measures are needed.

The data from these preliminary studies can be analyzed by statistical modeling and variable selection approaches, allowing us to come up with either a single mobility index or a relatively small number of mobility measures. These variables can then be used as the response variables of the original study. Second, the sample size for the study needs to be properly calculated. To do this, researchers need to specify the smallest meaningful difference between the intervention and control groups for each response variable. The next step is to check whether all model assumptions of the related sample size formula are valid. If not, then a new formula needs to be derived, which could be challenging.

For data collection, statisticians are vital in determining which study design is best, such as deciding between a double-blinded randomized study or other types of studies. These steps of study design are extremely important to make the collected data useful in testing the major scientific hypothesis. After data collection, much statistical expertise is required to analyze the data and make solid conclusions. During data analysis, proper statistical methods that clearly describe the observed data need to be chosen, all model assumptions should be verified, and develop new statistical methods when necessary.

Primary care physicians and geriatricians play an instrumental role in the identification of older adults who have or are at risk for impaired mobility. Unfortunately, healthcare providers encounter several barriers to the proper evaluation and treatment of mobility issues in older adults. Some of these barriers include insufficient knowledge in latest research findings in the field of geroscience, time constraints in busy clinics, lack of needed resources for treatment interventions, weak patient support systems, and even language barriers in some minority communities. Despite these barriers, most patients can be quickly and efficiently screened for cognitive concerns and/or mobility issues with validated assessments, such as the "get up and go" test. When appropriate, providers should deliver succinct but impactful counseling on the importance of adopting a healthy diet, practicing regular physical exercises, and obtaining adequate sleep. The use of educational hand-outs can be very helpful for some patients.

Clinicians should also use available resources for the enhancement of mobility, such as referrals to physical /occupational therapy, ophthalmology, audiology, and massage therapy.

There is a need for more educational programs for healthcare providers covering the latest research findings in the treatment of geriatric conditions including impaired mobility.

Optimal communication between clinical researchers and clinicians might facilitate the prompt implementation of efficacious new treatments. Collaboration among academic investigators and community partners also has the potential to increase the relevance of the research and its potential for addressing public problems such as general health disparities [313] and health problems more specific to seniors, such as limited mobility. Such collaborations require (a) culturally sensitive, multidisciplinary academic research teams, (b) empowerment of community members through training them to assume leadership in implementing and disseminating research center-tested J o u r n a l P r e -p r o o f interventions and assisting in getting the institutional review board credentials for being equal research partners, (c) paying trained community member researchers as research professionals, (d) mobilizing community resources and partners (e.g., businesses and local officials) to make policy changes to reduce the social determinants of health (e.g., no/limited public transportation in target low-income Black communities) that impede implementation and dissemination efforts.

Interventions shown to be efficacious in research centers are typically implemented and tested under controlled conditions with non-representative samples of motivated participants [314] . There is a need to implement and disseminate efficacious interventions in communities where uncontrollable social determinants of health (e.g., poverty, race and racism) and associated health disparities negatively influence the length and quality of community members' lives.

These communities are where seniors, racial/ethnic minorities, the poor, and/or the medically underserved (i.e., health disparity groups) often live. Because of this, ideal implementation and dissemination sites in such communities are churches [315, 316] and primary care centers [317] .

It is these sites that commonly serve the aforementioned groups, are stable community structures with physical resources (e.g., meeting spaces), and have human resources (e.g., pastors and physicians) who can influence members of health disparity groups to participate in efforts to implement and disseminate health promotion interventions.

The empirically supported community-based participatory research (CBPR) approach [318] is useful in implementing and disseminating efficacious interventions in communities in general and in racial/ethnic minority, poor, and/or medically underserved communities in particular. CBPR creates a paradigm shift from traditional research practices that have characterized academics as experts towards a collaborative research process in which academics are also learners [319] . Accordingly, the CBPR approach requires that community members be J o u r n a l P r e -p r o o f actively involved in all aspects of the research process, including the selection of the research topic and methodology, participant recruitment, research implementation, data collection, interpretation of study results, and dissemination of research findings [319, 320] .

The patient-centered culturally sensitive healthcare (PC-CSHC) model [317] , explains the linkages between provider cultural sensitivity and patients' health outcomes and is useful in guiding implementation and dissemination in community-based healthcare settings. Notably, cultural sensitivity extends beyond cultural competence and enables patients to feel comfortable with, trusting of, and respected by providers and researchers, and involves recognizing and overcoming biases and stereotypes that these groups have towards to each other [317] . The provider being culturally sensitive is one key aspect of the PC-CSHC model and is a major factor in health promotion. Further, patients must be allowed to determine what behaviors, methodologies, etc. enable them to feel comfort, trust and respect.

The other key aspect of this model is patient and community empowerment. In accordance with the PC-CSHC model, implementation and dissemination of research centertested interventions in community primary care sites that serve health disparity groups requiring that patients and community health workers are active partners with academic researchers. For example, patients should ideally be involved in focus groups and/or interviews to identify culturally sensitive strategies for making these efforts successful. Community health workers, physicians, and other providers can then (a) implement these strategies and disseminate the target interventions, and (b) participate with researchers in town hall meetings to disseminate information to the community about the impact of these interventions. Culturally diverse, multidisciplinary academic research teams can provide the training needed for physicians/providers and patients to be empowered, equitable partners in implementing and J o u r n a l P r e -p r o o f disseminating target interventions. Such empowerment by academic researchers is particularly important for patients such as minority, senior, poor, and medically underserved patients with limited actual and/or perceived power to take charge of their health. Patient empowerment is the appropriate response to the increasing national calls for social, health, and healthcare justice.

Can we really slow the decline in mobility that occurs during aging? And can function improve as we age? The good news is that the answer to both questions appears to be an emphatic yes. Effective future interventions, however, will need to take into consideration factors across multiple domains, as well as the complex interaction among these factors.

Findings over the past decade have highlighted the complexity of walking and how targeting multiple systems, including the brain and sensory organs, can have a dramatic effect on an older person's mobility and function. Additionally, several biological and behavioral factors have been identified as directly related to functional capacity.

These are exciting times within the field of Gerontology with novel discoveries happening across different fields of study that have direct implications for function and/or functional capacity. For example, the discoveries made within the biology of the aging realm have informed of the types of intervention targets that could truly make a difference in an older adult's functional capacity. Furthermore, COVID-19 has highlighted the importance of self-care and preventative medicine to promoting wellness and extend healthspan. COVID-19 has also highlighted the clear need to protect our older population, particularly minority older adults, as there are clear biological and metabolic factors that increase older adults' susceptibility to this condition. Additionally, COVID-19 has greatly increased the adoption of virtual communication;

J o u r n a l P r e -p r o o f thus, the acceptability of technologically based future interventions is likely to be much greater than prior to COVID-19.

Before translating interventions on a broad scale, however, their suitability and effectiveness across a number of domains are needed to help inform decision making. Clearly, there is an important need to evaluate safety outcomes, first and foremost, with the next benchmark related to whether such interventions are sustainable. There is also the need to carefully determine the types of randomized clinical trials that are best suited to address particular questions, as well as the appropriate comparison groups.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Highlights • Findings over the past decade have highlighted the complexity of walking and how targeting multiple systems, including the brain and sensory organs, as well as the environment in which a person lives, can have a dramatic effect on an older person's mobility and function.

• Behavioral interventions that incorporate complex walking tasks and other activities of daily living appear to be especially helpful for improving mobility function.

• Effective future interventions, however, will need to take into consideration factors across multiple domains, as well as the complex interaction among these factors.

• Before translating interventions on a broad scale, however, their suitability and effectiveness across a number of domains are needed to help inform decision making. 

Active life expectancy

Geroscience: linking aging to chronic disease

Age-Related Change in Mobility: Perspectives From Life Course Epidemiology and Geroscience

Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity

Translational geroscience: emphasizing function to achieve optimal longevity

A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME

United Nations World Populations Prospects: The

Advances in geroscience: impact on healthspan and chronic disease

Successful aging: Advancing the science of physical independence in older adults

The impact of behavioral intervention on obesity mediated declines in mobility function: implications for longevity

Studies of Illness in the Aged. The Index of Adl: A Standardized Measure of Biological and Psychosocial Function

A Guttman health scale for the aged

Role of gait speed in the assessment of older patients

Improvement in usual gait speed predicts better survival in older adults

Obesity, functional mobility and quality of life

Ability to walk 1/4 mile predicts subsequent disability, mortality, and health care costs

Association of mobility limitations with health care satisfaction and use of preventive care: a survey of Medicare beneficiaries

Estimating transition probabilities in mobility and total costs for medicare beneficiaries

Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability

Disability status, mortality, and leading causes of death in the United States community population

Active life expectancy for 10,000 Caucasian men and women in three communities

Sedentary activity associated with metabolic syndrome independent of physical activity. Diabetes Care

Increasing prevalence of the metabolic syndrome among u.s. Adults. Diabetes Care

Prevalence of the metabolic syndrome in US populations

Lumbar motoneurons of man: I) number and diameter histogram of alpha and gamma axons of ventral root

Macro EMG in healthy subjects of different ages

Methods for estimating numbers of motor units in biceps-brachialis muscles and losses of motor units with aging

Physiological changes in ageing muscles

The estimated numbers and relative sizes of thenar motor units as selected by multiple point stimulation in young and older adults

Motor unit number estimates in the tibialis anterior muscle of young, old, and very old men

Role of the nervous system in sarcopenia and muscle atrophy with aging: strength training as a countermeasure

Innervation and neuromuscular control in ageing skeletal muscle

Denervation drives mitochondrial dysfunction in skeletal muscle of octogenarians

Accumulation of severely atrophic myofibers marks the acceleration of sarcopenia in slow and fast twitch muscles

Failed reinnervation in aging skeletal muscle

Multimodal Imaging of Brain Activity to Investigate Walking and Mobility Decline in Older Adults

Neural correlates of obstacle negotiation in older adults: An fNIRS study. Gait and Posture

Neurocognitive Aging and the Compensation Hypothesis

Automaticity of walking: functional significance, mechanisms, measurement and rehabilitation strategies

The Global Burden of Musculoskeletal Pain-Where to From Here?

Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study

Prevalence of chronic benign pain disorder among adults: a review of the literature

Movement-evoked pain: transforming the way we understand and measure pain

Physical performance and movement-evoked pain profiles in communitydwelling individuals at risk for knee osteoarthritis

Interrelated neuromuscular and clinical risk factors that contribute to falls

Multisite Pain Is Associated with Long-term Patient-Reported Outcomes in Older Adults with Persistent Back Pain

Persistent Pain Quality as a Novel Approach to Assessing Risk for Disability in Community-Dwelling Elders with Chronic Pain

Risk factors for restriction in activity associated with fear of falling among seniors within the community

The course of limitations in activities over 5 years in patients with knee and hip osteoarthritis with moderate functional limitations: risk factors for future functional decline. Osteoarthritis Cartilage

Profile of the elderly in physical therapy and its relation to functional disability

Reasons for functional decline despite reductions in knee pain: the Multicenter Osteoarthritis Study

Chronic pain, perceived stress, and cellular aging: an exploratory study

Accelerated aging in adults with knee osteoarthritis pain: consideration for frequency, intensity, time, and total pain sites

Chronic pain is associated with a brain aging biomarker in communitydwelling older adults

Epigenetic aging is associated with clinical and experimental pain in community-dwelling older adults

Clinical neurophysiology of circadian rhythm sleep-wake disorders

Age-Related Changes in the Circadian System Unmasked by Constant Conditions. eNeuro

Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents

The Role of the Molecular Clock in Promoting Skeletal Muscle Growth and Protecting against Sarcopenia

A new face of sleep: The impact of post-learning sleep on recognition memory for face-name associations

The aging clock: circadian rhythms and later life

Mitochondrial Mechanisms of Neuromuscular Junction Degeneration with Aging. Cells

A cross-sectional study of muscle strength and mass in 45-to 78-yr-old men and women

Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health

Muscle function decline and mitochondria changes in middle age precede sarcopenia in mice

Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway

Skeletal muscle mitochondria and aging: a review

Circadian Rhythms and Mitochondria: Connecting the Dots

Executive Summary: Heart Disease and Stroke Statistics--2016 Update: A Report From the American Heart Association

Aortic stiffness and interstitial myocardial fibrosis by native T1 are independently associated with left ventricular remodeling in patients with dilated cardiomyopathy

Arterial-ventricular coupling with aging and disease

Concept of Extremes in Vascular Aging

Enhancing Recovery From Sepsis: A Review

Large cross-sectional study of presbycusis reveals rapid progressive decline in auditory temporal acuity

WHO, Prevention of blindness and deafness: Estimates

Current concepts in age-related hearing loss: epidemiology and mechanistic pathways

The role of hormones, cytokines and heat shock proteins during age-related muscle loss

Growth Hormone in Aging. The Endocronology of Aging

Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging

Bone mineral status and bone loss over time in men with chronic systolic heart failure and their clinical and hormonal determinants

Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEA-S), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty

Hospital diagnoses, Medicare charges, and nursing home admissions in the year when older persons become severely disabled

Disability in older adults: evidence regarding significance, etiology, and risk

Morbidity and disability in older persons in the years prior to death

Functional transitions among the elderly: patterns, predictors, and related hospital use

Sarcopenic obesity and complex interventions with nutrition and exercise in community-dwelling older persons--a narrative review

The State of US Health, 1990-2016: Burden of Diseases, Injuries, and Risk Factors Among US States

Does overall diet in midlife predict future aging phenotypes? A cohort study. The American journal of medicine

The association between objectively measured sitting and standing with body composition: a pilot study using MRI

Associations of physical activity and sedentary behavior with regional fat deposition

Reduced physical activity increases intermuscular adipose tissue in healthy young adults

Sedentary behavior, physical activity, and the metabolic syndrome among U.S. adults

Low muscle mass in older men: the role of lifestyle, diet and cardiovascular risk factors

Physical activity prevented functional decline among frail community-living elderly subjects in an international observational study

Obesity and mobility disability in the older adult

Decreased functional capacity and muscle strength in elderly women with metabolic syndrome

Prevalence of Metabolic Syndrome and Its Association with Physical Capacity, Disability, and Self-Rated Health Among Lifestyle Interventions for Elders (LIFE) Study Participants

Sedentary and physically active behavior patterns among low-income African-American and white adults living in the southeastern United States

The independent and combined associations of physical activity and sedentary behavior with obesity in adults: NHANES 2003-06

Sedentary time is associated with the metabolic syndrome in older adults with mobility limitations--The LIFE Study

Why sleep is important for health: a psychoneuroimmunology perspective

Prevalence of Healthy Sleep Duration among Adults--United States

Sleep and Human Aging

Frequent napping is associated with excessive daytime sleepiness, depression, pain, and nocturia in older adults: findings from the National Sleep Foundation '2003 Sleep in America' Poll

Longitudinal relationship between sleep deficiency and pain symptoms among community-dwelling older adults in Japan and Singapore

Cortical thickness mediates the association between self-reported pain and sleep quality in community-dwelling older adults

Chronic Musculoskeletal Pain Moderates the Association between Sleep Quality and Dorsostriatal-Sensorimotor Resting State Functional Connectivity in Community-Dwelling Older Adults

The National Institute on Aging Health Disparities Research Framework

Effects of stress throughout the lifespan on the brain, behaviour and cognition

Social Isolation and Loneliness in Older Adults: Opportunities for the Health Care System

Associations between social isolation, loneliness, and objective physical activity in older men and women

Social isolation, loneliness, and all-cause mortality in older men and women

Social isolation, loneliness and health in old age: a scoping review

Where we live: health care in rural vs urban America

Differential access to care: The role of age, insurance, and income on race/ethnicity-related disparities in adult perforated appendix admission rates

National dissemination of multiple evidence-based disease prevention programs: reach to vulnerable older adults

Ethnicity-and socio-economic status-related stresses in context: an integrative review and conceptual model

Determinants of Adherence in Time-Restricted Feeding in Older Adults: Lessons from a Pilot Study

Older Adults' Perceptions of Mobility: A Metasynthesis of Qualitative Studies

Frailty Phenotype: Evidence of Both Physical and Mental Health Components in Community-Dwelling Early-Old Adults

Balance Confidence and Fear of Falling Avoidance Behavior Are Most Predictive of Falling in Older Adults: Prospective Analysis

Self-efficacy, pain, and quadriceps capacity at baseline predict changes in mobility performance over 2 years in women with knee osteoarthritis

Falls efficacy as a measure of fear of falling

Dizziness and its association with walking speed and falls efficacy among older men and women in an urban population

Falls and fear of falling: which comes first? A longitudinal prediction model suggests strategies for primary and secondary prevention

Mobility device use in older adults and incidence of falls and worry about falling: findings from the 2011-2012 national health and aging trends study

Effects of supervised slackline training on postural instability, freezing of gait, and falls efficacy in people with Parkinson's disease

A Backward Walking Training Program to Improve Balance and Mobility in Acute Stroke: A Pilot Randomized Controlled Trial

Integrated primary and geriatric care for frail older adults in the community: Implementation of a complex intervention into real life

Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss

One-Year Adherence to the Otago Exercise Program With or Without Motivational Interviewing in Community-Dwelling Older Adults

Walking can be more effective than balance training in fall prevention among community-dwelling older adults

The Effect of Yoga on Balance and Fear of Falling in Older Adults

Motivating Older Adults with Cancer to Keep Moving: the Implications of Lifestyle Interventions on Physical Activity

Attitudes and needs of residents in long-term care facilities regarding physical activity-A systematic review and synthesis of qualitative studies

Enablers and barriers to older people's participation in strength and balance activities: A review of reviews

Integrated care for geriatric frailty and sarcopenia: a randomized control trial

The retardation of aging by caloric restriction: studies in rodents and primates

Dietary restriction and lifespan: Lessons from invertebrate models

Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans

Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial

Caloric restriction alone and with exercise improves CVD risk in healthy nonobese individuals

Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects

Calorie restriction increases muscle mitochondrial biogenesis in healthy humans

Weighty concerns: the growing prevalence of obesity among older adults

The danger of weight loss in the elderly

The future of obesity: new drugs versus lifestyle interventions

Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting

Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms

Mediterranean Dietary Patterns and Impaired Physical Function in Older Adults

Association Between Adherence to the Mediterranean Diet at Midlife and Healthy Aging in a Cohort of French Adults

The effects of the ketogenic diet on behavior and cognition

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

A Ketogenic Diet Improves Cognition and Has Biochemical Effects in Prefrontal Cortex That Are Dissociable From Hippocampus

Physical activity and risk of cognitive impairment among older persons living in the community

Walking speed predicts health status and hospital costs for frail elderly male veterans

Aerobic exercise effects on cognitive and neural plasticity in older adults

Genomic comparison of the ants Camponotus floridanus and Harpegnathos saltator

The effect of walking on lower body disability among older blacks and whites

Risk of functional decline among well elders

Maintaining mobility in late life. II. Smoking, alcohol consumption, physical activity, and body mass index

Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial

Resistance training for activity limitations in older adults with skeletal muscle function deficits: a systematic review

Effects of a Fall Prevention Exercise Program on Muscle Strength and Balance of the Old-old Elderly

Is lower extremity strength gain associated with improvement in physical performance and disability in frail, community-dwelling elders?

Molecular Transducers of Physical Activity Consortium (MoTrPAC): Mapping the Dynamic Responses to Exercise

Reducing Sedentary Behavior Versus Increasing Moderate-to-Vigorous Intensity Physical Activity in Older Adults

Breaking-up sedentary time is associated with physical function in older adults

Intervening to reduce sedentary behavior in older adults -pilot results

Not just another walking program

Interventions to reduce sedentary behavior

Mobility after hospital discharge as a marker for 30-day readmission

Systematic review of functional training on muscle strength, physical functioning, and activities of daily living in older adults

A technical guide to tDCS, and related non-invasive brain stimulation tools

Effects of noninvasive brain stimulation on cognitive function in healthy aging and Alzheimer's disease: a systematic review and meta-analysis

Time-but not sleep-dependent consolidation of tDCS-enhanced visuomotor skills

Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation

Enhancing Working Memory Training with Transcranial Direct Current Stimulation

Cognitive Interventions. Handbook of the psychology of aging

Neuropsychology of aging

Characterizing and Assessing Cognitive Aging. Cognitive Aging: progress in understanding and opportunities for action

Training versus engagement as paths to cognitive enrichment with aging

Computer and Videogame Interventions for Older Adults' Cognitive and Everyday Functioning

The impact of sustained engagement on cognitive function in older adults: the Synapse Project

Individualized piano instruction enhances executive functioning and working memory in older adults

Training Older Adults to Use Tablet Computers: Does It Enhance Cognitive Function? Gerontologist

Can Acquired Skill and Technology Mitigate Age-Related Declines in Learning Rate? Current and Emerging trends in aging and work

Interventions to Prevent Age-Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer's-Type Dementia

Effects of cognitive training interventions with older adults: a randomized controlled trial

Useful field of view test

WiiFit Plus balance test scores for the assessment of balance and mobility in older adults

Predictors of falling in older Maryland drivers: a structural-equation model

Cognitive training decreases motor vehicle collision involvement of older drivers

Benefits of cognitive dual-task training on balance performance in healthy older adults

Effects of single-task versus dual-task training on balance performance in older adults: a double-blind, randomized controlled trial

Standardization in the MSPE: Key Tensions for Learners, Schools, and Residency Programs

Chronic oxytocin administration as a tool for investigation and treatment: A cross-disciplinary systematic review

Oxytocin alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men

Sniffing neuropeptides: a transnasal approach to the human brain

Evidence for intranasal oxytocin delivery to the brain: recent advances and future perspectives

A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research

Oxytocin and socioemotional aging: Current knowledge and future trends

Oxytocin modulates meta-mood as a function of age and sex. Front Aging Neurosci

Ageing and oxytocin: a call for extending human oxytocin research to ageing populations--a mini-review

Lifespan oxytocin signaling: Maturation, flexibility, and stability in newborn, adolescent, and aged brain

Oxytocin control of maternal behavior. Regulation by sex steroids and offspring stimuli

Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine

Treatment of obesity and diabetes using oxytocin or analogs in patients and mouse models

Musculoskeletal Pain and Brain Morphology: Oxytocin's Potential as a Treatment for Chronic Pain in Aging. Front Aging Neurosci

Oxytocin's fingerprint in personality traits and regional brain volume

Alterations of brain volumes in women with early life maltreatment and their associations with oxytocin

Associations between oxytocin receptor gene (OXTR) methylation, plasma oxytocin, and attachment across adulthood

Repeated treatment with oxytocin promotes hippocampal cell proliferation, dendritic maturation and affects socio-emotional behavior

Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration

Effects of a 10-day oxytocin trial in older adults on health and well-being

Plasma oxytocin and vasopressin levels in young and older men and women: Functional relationships with attachment and cognition

Current nutritional and pharmacological anti-aging interventions

Metformin as a Tool to Target Aging

Pharmaceutical intervention mobility aging decline Locomotion and Posture in Older Adults

Metformin and Aging: A Review

Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans

NAD+ metabolism in health and disease

Impairment of an Endothelial NAD(+)-H2S Signaling Network Is a Reversible Cause of

NAD(+) Intermediates: The Biology and Therapeutic Potential of NMN and NR

Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults

Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans

Fat mobilization without weight loss is a potentially rapid response to nicotinamide riboside in obese people: it's time to test with exercise

Nicotinamide riboside-A missing piece in the puzzle of exercise therapy for older adults?

The mechanisms of massage and effects on performance, muscle recovery and injury prevention

Fascial well-being: Mechanotransduction in manual and movement therapies

Mechanotransduction and the regulation of protein synthesis in skeletal muscle

Mechanical strain stabilizes reconstituted collagen fibrils against enzymatic degradation by mammalian collagenase matrix metalloproteinase 8 (MMP-8)

Manual therapy as an effective treatment for fibrosis in a rat model of upper extremity overuse injury

Effect of therapeutic massage on insomnia and climacteric symptoms in postmenopausal women

A randomised study of the effects of massage therapy compared to guided relaxation on well-being and stress perception among older adults

Massage Therapy for Pain-Call to Action

Nonpharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline

Massage therapy in chronic musculoskeletal pain managment: a scooping review of the literature

Noninvasive nonpharmacological treatment for chronic pain: a systematic review

Agency for Healthcare Research and Quality

Massage timing affects postexercise muscle recovery and inflammation in a rabbit model

Could Intermittent Energy Restriction and Intermittent Fasting Reduce Rates of Cancer in Obese, Overweight, and Normal-Weight Subjects? A Summary of Evidence

A preliminary study of the effects of a single session of Swedish massage on hypothalamic-pituitary-adrenal and immune function in normal individuals

A preliminary study of the effects of repeated massage on hypothalamic-pituitary-adrenal and immune function in healthy individuals: a study of mechanisms of action and dosage

The role of DNA methylation in epigenetics of aging

Massage therapy attenuates inflammatory signaling after exercise-induced muscle damage

The Effect of Foam Rolling of the Hamstrings on Proprioception at the Knee and Hip Joints

Effects of Massage on Muscular Strength and Proprioception After Exercise-Induced Muscle Damage

The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know

Massage Therapy Produces Short-term Improvements in Balance, Neurological, and Cardiovascular Measures in Older Persons

The physiological and psychological effects of slow-stroke back massage and hand massage on relaxation in older people

Long-Term Adherence to Health Behavior Change

Tech Adoption Climbs Among Older Americans

Demographics of Mobile Device Ownership and Adoption in the United States

IDC Forecasts Steady Double-Digit Growth for Wearables as New Capabilities and Use Cases Expand the Market Opportunities. IDC

About one-in-five Americans use a smart watch or fitness tracker

Perception of Older Adults Toward Smartwatch Technology for Assessing Pain and Related Patient-Reported Outcomes: Pilot Study

Criteria for assessing the quality of mHealth apps: a systematic review

A Path to Better-Quality mHealth Apps

The Impact of mHealth Interventions: Systematic Review of Systematic Reviews

Mobile Health Technology for Atrial Fibrillation Management Integrating Decision Support, Education, and Patient Involvement: mAF App Trial

Efficacy of telemedical interventional management in patients with heart failure (TIM-HF2): a randomised, controlled, parallel-group, unmasked trial

The effectiveness of remote monitoring of elderly patients after hospitalisation for heart failure: The renewing health European project

Healthy aging: The ultimate preventative medicine

Integrating Mobile-health, health coaching, and physical activity to reduce the burden of chronic low back pain trial (IMPACT): a pilot randomised controlled trial

Smartphone Cognitive Behavioral Therapy as an Adjunct to Pharmacotherapy for Refractory Depression: Randomized Controlled Trial

Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

Online cancer communication: meeting the literacy, cultural and linguistic needs of diverse audiences

Evaluating health communication programs to enhance health care and health promotion

Unpacking mHealth interventions: A systematic review of behavior change techniques used in randomized controlled trials assessing mHealth effectiveness. Digit Health

Age-dependent changes in mobility and separation of the nematode Caenorhabditis elegans

Identification by machine vision of the rate of motor activity decline as a lifespan predictor in C. elegans. Neurobiology of aging

Drosophila as a model for age-related impairment in locomotor and other behaviors

Age-Related Change in Mobility: Perspectives From Life Course Epidemiology and Geroscience. The journals of gerontology Series A, Biological sciences and medical sciences

Age-dependent changes in mobility and separation of the nematode Caenorhabditis elegans

Age-dependent changes and biomarkers of aging in Caenorhabditis elegans

Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature

Functional aging in the nervous system contributes to age-dependent motor activity decline in C. elegans

Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults

Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle

Autophagy in the cellular energetic balance

Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise

Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling

Molecular inflammation: underpinnings of aging and age-related diseases

Effect of dietary restriction and exercise on lower extremity tissue compartments in obese, older women: a pilot study

Hypothalamic-pituitary-adrenal axis function and corticosterone receptor expression in behaviourally characterized young and aged Long-Evans rats

Aging, the central nervous system, and mobility

Mobility in older adults: a comprehensive framework

Health Care Use and Barriers to Care among Latino Immigrants in a New Migration Area. J Health Care Poor Underserved

Quality-of-care research: internal elegance and external relevance

Obesity interventions in African American faith-based organizations: a systematic review

Engaging Black Churches to Address Cancer Health Disparities: Project CHURCH. Front Public Health

Counseling Psychologists and Behavioral Health: Promoting Mental and Physical Health Outcomes. Sage journals

Community-Based Participatory Research Conceptual Model: Community Partner Consultation and Face Validity

The Three R's: How Community Based Participatory Research Strengthens the Rigor

Community-based participatory research from the margin to the mainstream: are researchers prepared? Circulation