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

Abstract

Most nations of the world are undergoing rapid and dramatic population ageing, which presents great socio‐economic challenges, as well as opportunities, for individuals, families, governments and societies. The prevailing biomedical strategy for reducing the healthcare impact of population ageing has been ‘compression of morbidity’ and, more recently, to increase healthspan, both of which seek to extend the healthy period of life and delay the development of chronic diseases and disability until a brief period at the end of life. Indeed, a recently established field within biological ageing research, ‘geroscience’, is focused on healthspan extension. Superimposed on this background are new attitudes and demand for ‘optimal longevity’ – living long, but with good health and quality of life. A key obstacle to achieving optimal longevity is the progressive decline in physiological function that occurs with ageing, which causes functional limitations (e.g. reduced mobility) and increases the risk of chronic diseases, disability and mortality. Current efforts to increase healthspan centre on slowing the fundamental biological processes of ageing such as inflammation/oxidative stress, increased senescence, mitochondrial dysfunction, impaired proteostasis and reduced stress resistance. We propose that optimization of physiological function throughout the lifespan should be a major emphasis of any contemporary biomedical policy addressing global ageing. Effective strategies should delay, reduce in magnitude or abolish reductions in function with ageing (primary prevention) and/or improve function or slow further declines in older adults with already impaired function (secondary prevention). Healthy lifestyle practices featuring regular physical activity and ideal energy intake/diet composition represent first‐line function‐preserving strategies, with pharmacological agents, including existing and new pharmaceuticals and novel ‘nutraceutical’ compounds, serving as potential complementary approaches. Future research efforts should focus on defining the temporal patterns of functional declines with ageing, identifying the underlying mechanisms and modulatory factors involved, and establishing the most effective lifestyle practices and pharmacological options for maintaining function. Continuing development of effective behavioural approaches for enhancing adherence to healthy ageing practices in diverse populations, and ongoing analysis of the socio‐economic costs and benefits of healthspan extension will be important supporting goals. To meet the demands created by rapid population ageing, a new emphasis in physiological geroscience is needed, which will require the collaborative, interdisciplinary efforts of investigators working throughout the translational research continuum from basic science to public health.

Population ageing and chronic disease

Among the many great societal challenges, one could make a strong case that the rapid ageing of the world's population is the most important problem of our time. Indeed, population ageing has been described as a ‘ticking time bomb’ that is bringing a healthcare crisis equivalent in scale to global warming (Petsko, 2008; Olshansky et al. 2009). In the developed countries of the world, by the year 2050 at least 25% of the population will be older than 65 years of age, with some regions exceeding 40% (Petsko, 2008; Harper, 2014). Here in the U.S., the number of adults aged 65 and over is expected to double during this period, and those 80 years of age and older will at least triple – from ∼10 million to over 30 million (Petsko, 2008; Vincent & Velkoff, 2010). The changing demographics of ageing worldwide are being driven by increases in life expectancy, but also by declines in birth rates and infant mortality, particularly in developing nations (Chatterji et al. 2014; Harper, 2014).

We are living much longer than our ancestors in large part because of reduced early mortality from causes such as infectious diseases, accidents and malnutrition. However, our newfound longevity comes at a price. For the first time in history we are living long enough to encounter a different set of disorders – chronic degenerative diseases. Heart disease, stroke, cancer, diabetes, kidney disease and Alzheimer's and Parkinson's diseases are now the leading causes of morbidity and mortality in modern societies, and ageing is the major risk factor driving all of these pathologies. Moreover, because advancing age is the common causal influence, these chronic disorders often are occurring together as so‐called ‘comorbidities of ageing’. Although ageing is the primary factor driving chronic diseases and these disorders are, therefore, diseases of ageing, it is important to emphasize that ageing itself is not a disease (Kirkwood, 2005; Hayflick, 2007). Unlike any clinical disease, ageing is a unique, natural biological process that occurs in all members of all species of multicellular animals after reproductive maturation is achieved (Hayflick, 2007). Nevertheless, while not a disease, ageing does increase our vulnerability for disease.

Based on the combination of marked increases in the number of older adults in the coming decades and the shift in the major causes of morbidity, it is clear that much of the world is facing a new epidemic of chronic diseases in the coming decades. It recently was estimated for example that by 2040, 40% of all adults in the U.S. will have at least one form of clinical cardiovascular disease (CVD; Heidenreich et al. 2011), 15 million will have some form of dementia and 3 million will be diagnosed with Parkinson's Disease (Petsko, 2008; Kowal et al. 2013). The expected increases in these and other age‐associated conditions will have important consequences for society including greater caregiving and financial burden for families, increased pressure on government health insurance programmes and entitlement budgets, unprecedented stress on our healthcare facilities and personnel, and changes to labour markets, saving and consumption, housing and transport, and many other facets of community life (Olshansky et al. 2009; Beard & Bloom, 2014; Harper, 2014). Despite the magnitude and certainty of the problem, referred to variously as the ‘Silver Tsunami’ and ‘a healthcare asteroid hurtling towards earth’, no comprehensive plan has been developed to deal with its impact.

Compression of morbidity, healthspan and optimal longevity

For the last three decades, the primary strategy in gerontology and geriatric medicine for lessening the impending health care dilemma from population ageing has been the compression of morbidity. Advanced by James Fries originally in 1980 (Fries, 1980), this strategy posits that by delaying the age of onset of chronic diseases and disability more than any associated increase in survival, we can limit morbidity to a shorter period closer to the natural end of life, thus reducing the total amount of incurred illness and disability (i.e. area under the morbidity curve).

More recently, several thought leaders with interest in the biology of ageing, a field of biomedical ageing research historically focused on the study of fundamental genetic, molecular and cellular mechanisms of ageing and lifespan extension, have borrowed from the theory of compression of morbidity to promote the concept of healthspan (Kirkland & Peterson, 2009; Seals & Melov, 2014 a). Healthspan is the period of life free of major chronic clinical diseases and disability. The main concept is that life can be divided roughly into two phases: a period of relatively healthy ageing (healthspan) and a period of age‐associated disease and disability (Blagosklonny, 2012; Seals & Melov, 2014 a) (Fig. 1). Although recent medical advances have resulted in increased mean lifespan, it is argued that this is mainly the result of surviving longer with age‐associated disease and disability, rather than by increasing healthspan (Blagosklonny, 2012; Goldman et al. 2013; Harper, 2014). Healthspan has become the central theme of the newly named area of biological ageing research termed geroscience, and the primary objective of geroscience advocates is to identify the biological mechanisms and strategies that will increase healthspan (Kirkland & Peterson, 2009; Burch et al. 2014; Kennedy et al. 2014).

Figure 1. Compression of morbidity, healthspan and optimal longevity .

A, delaying the age of onset of chronic diseases and disability (morbidity) longer than any associated increase in lifespan results in ‘compression’ of the overall morbidity incurred in a lifetime. B, healthspan is a period of healthy ageing with a modestly increasing (‘subclinical’) chronic disease burden, followed by a period of age‐related clinical disease. To achieve optimal longevity (living long, but primarily in wellness) in the future, healthspan must be significantly extended. Modified from Blagosklonny (2012).

Beyond concerns of the expected health care crisis associated with population ageing, there is another superimposed pressure for increasing healthspan and compressing morbidity – the attitudes and goals of the individuals presently undergoing the ageing process (Kirkland, 2013; Seals & Melov, 2014 a). Many of those nearing traditional ages of retirement today have very different views about growing older than their predecessors. As illustrated by the high‐profile baby boomer generation, i.e. adults born between 1946 and 1964, most individuals moving through late middle‐age/older adulthood today have a strong interest in remaining healthy, active, productive and independent until the very end of life (although many do not follow recommended guidelines for achieving these states). The general goal is to live long, but well – an outcome that could be termed optimal longevity (Seals & Melov, 2014 a). When considered in combination with healthcare concerns related to population ageing, this strong desire among individuals for optimal longevity is further stimulating the demand for healthspan‐extending strategies, interventions and treatments.

Healthspan and physiological function with ageing

A major obstacle to achieving increased healthspan, compression of morbidity and optimal longevity in both individuals and populations is the decline in physiological function that occurs with advancing age (Beard & Bloom, 2014; Seals & Melov, 2014 a,b). These impairments lead to functional limitations, increased risk of chronic diseases and disability, reduced productivity/independence/quality of life, and an increased risk of mortality (Fried et al. 2009; Seals & Melov, 2014,b). The impaired physiological function of ageing poses a threat to healthspan and optimal longevity from several perspectives.

Some of the healthspan‐impacting effects of age‐associated physiological dysfunction can be viewed as independent of clinical disease. For example, an accelerated reduction in muscle strength/power with ageing, perhaps driven by interactive factors such as motor unit loss/reorganization, sarcopenia (muscle wasting) and decreased physical activity (Morley et al. 2001; Doherty, 2003; Reid & Fielding, 2012; Manini et al. 2013) can eventually lead to functional limitations like reduced mobility and the ability to perform basic activities of daily living. Similarly, age‐associated reductions in cardiac systolic performance combined with progressive decreases in maximal heart rate reduce maximal cardiac output and aerobic exercise capacity (Tanaka & Seals, 2008). These types of changes begin to influence functional status and quality of life, and can worsen into more fully developed medical disability, with resulting further impairments in function (Fig. 2 A).

Figure 2. Physiological dysfunction with ageing as a threat to healthspan and optimal longevity .

Impaired physiological function with ageing: can lead to functional limitations and disability, independent of clinical disease (A), increases the risk of clinical diseases (B) and predicts mortality (C).

Impaired physiological function is also an underappreciated ‘gateway’ to the chronic degenerative diseases of ageing (Seals & Melov, 2014 a,b; Fig. 2 B). Numerous examples of reduced function leading to increased risk of disease exist. Vascular dysfunction is the major risk factor for age‐associated CVD (Lakatta & Levy, 2003 b), and is a primary pathological process in the aetiology of Alzheimer's Disease (Kalaria, 1999; Selley, 2003; Dickstein et al. 2010). Peripheral insulin resistance related to increases in adiposity with ageing can lead to pancreatic β‐cell dysregulation and increases risk of type 2 diabetes mellitus (Chang & Halter, 2003; Wilson et al. 2005; Neeland et al. 2012). Reductions in glomerular filtration rate with ageing increase the risk of developing chronic kidney disease, end‐stage renal disease and CVD (Anderson et al. 2009). Impaired diastolic filling of the left ventricle with age, a key feature of cardiac ageing (Lakatta & Levy, 2003 a), increases the likelihood of developing heart failure with preserved ejection fraction, a common form of chronic heart failure observed clinically (Aurigemma et al. 2001; Lam et al. 2011). At the cellular level, T and B immune cell dysfunction with ageing increases our risk of disease via the seemingly paradoxical development of immunosuppression and sterile inflammation (Chung et al. 2009; Weiskopf et al. 2009), dysregulated cellular growth and differentiation raise our likelihood of cancer (Hanahan & Weinberg, 2000; Jemal et al. 2010), and neuronal dysfunction increases vulnerability for dementia (Blessed et al. 1968).

In the end, a vicious cycle of declines in physiological function leading to chronic disease leading to further reductions in function develops. Vascular dysfunction causing CVD, which, in turn, worsens vascular dysfunction, is a good example. Importantly, a single adverse change in physiological function can result in widespread clinical pathology. Stiffening of the large elastic arteries (aorta and carotid arteries) with age, a hallmark of vascular ageing (Lakatta & Levy, 2003 b), has now been linked to a remarkable number of common chronic disorders of advancing age including systolic hypertension, coronary artery disease, chronic kidney disease, stroke, cognitive impairment, Alzheimer's Disease and motor dysfunction, including falls (Mitchell et al. 2010; Brunner et al. 2011; Tsao et al. 2013).

In addition to disease, impaired physiological function with ageing is also a well‐established, independent predictor of mortality (Fig. 2 C; Seals & Melov, 2014 a). For example, in late‐middle‐aged/older adults, cardiorespiratory fitness (aerobic exercise capacity) (Lee et al. 2011; Vigen et al. 2012), gait speed (Studenski et al. 2011), grip strength (Rantanen et al. 2012) and integrative neuromuscular tasks, such as the ability to sit and rise from the floor (de Brito et al. 2012), all are predictive of survival, independent of other risk factors.

In a broad sense, as physiological function declines with ageing, functional status is reduced and the risk of morbidity, disability and mortality increase. As such, age‐associated decreases in physiological function should be viewed as a critical target for the approaching pandemic of chronic disease and disability facing developed, as well as many developing nations of the world (Beard & Bloom, 2014; Seals & Melov, 2014 a, b).

‘Slowing ageing’ as a broad approach for increasing healthspan

Historically, medicine has focused largely on diagnosis and treatment of clinical diseases, although in recent decades a greater emphasis has been placed on health maintenance and the prevention of chronic diseases. Efforts to prevent chronic diseases generally have taken an approach similar to that used successfully to dramatically reduce the prevalence of infectious diseases in the previous century, namely, by targeting specific disorders. However, a growing school of thought in the fields of ageing biology, biomedicine and healthcare economics suggests that such an approach will be far less successful for preventing chronic diseases in the future (Holliday, 1984; Butler et al. 2008; Olshansky et al. 2009; Goldman et al. 2013; Kirkland, 2013). The argument is that infectious diseases often occurred in the past as individual illnesses, whereas the long‐lived adults of today are likely to develop multiple, often simultaneous chronic disorders. As such, preventing a particular chronic disease (e.g. cancer) will have only a modest effect on mean life expectancy because another comorbidity (e.g. CVD) will simply ‘backfill’ the reduction in mortality risk caused by prevention of the targeted disease. Most importantly, the approach to preventing diseases one at a time would not obviously increase healthspan for the simple reason that healthspan is determined primarily by ageing itself. Rather, current thinking in the field of ageing for extending healthspan has shifted to the strategic approach of slowing the broad effects of ageing on chronic diseases by interfering with the fundamental biological processes by which ageing increases our risk of developing these disorders in the first place. Stated another way, instead of attempting to prevent individual chronic diseases, the idea is to delay the clinical manifestation of all of these disorders as a group by inhibiting the basic mechanisms of ageing (Seals & Melov, 2014 a) (Fig. 3).

Figure 3. Slowing processes of ageing as a strategy for increasing healthspan .

Delaying age‐related disorders as a group may be a more effective way to increase healthspan than preventing or treating individual chronic diseases. The former would involve inhibiting the basic mechanisms of ageing.

The results of a recent analysis suggest that significant health and economic benefits would be realized from such an approach compared with current strategies for prevention of individual diseases (Goldman et al. 2013). In this analysis, a microsimulation was performed using the Future Elderly Model to predict future medical spending, health conditions, functional status and other outcomes in representative cohorts of older adults. The findings indicate that slowing ageing would delay the age of onset of all major chronic diseases by a mean of 7 years, thus significantly increasing healthspan, quality of life, and the ability to remain productive in the workforce. Delaying ageing would, however, require gradually increasing the eligibility age for government entitlement programmes to offset costs associated with increased life expectancy.

Assuming this theory has merit, what are the fundamental processes of ageing that need to be slowed or delayed to extend healthspan? The basic biological mechanisms of ageing remain under intense investigation, but several processes have been identified based largely on work in model organisms, as summarized in recent reviews on the topic (Lopez‐Otin et al. 2013; de Cabo et al. 2014; Kennedy et al. 2014; Fig. 3). Among the putative mechanisms contributing to ageing phenotypes, including impairments in physiological function, are oxidative stress, chronic low‐grade inflammation (‘inflammageing’), mitochondrial dysfunction, cellular senescence, dysregulated cellular energy sensing/growth pathways (AMPK, NAD⁺‐sirtuin, mTOR, IGF‐1), impaired proteostasis (autophagy, etc.), epigenetic modifications, impaired stem cell function/bioavailability, genomic instability/macromolecular damage, telomere attrition and reduced adaptation to stress (impaired upregulation of stress resistance pathways) (Vijg & Campisi, 2008; Chung et al. 2009; Lopez‐Otin et al. 2013; Newgard & Sharpless, 2013; Kennedy et al. 2014).

These processes interfere with normal physiological cell signalling, requiring compensatory adjustments as we age in order to maintain homeostasis, e.g. increased β‐cell insulin secretion to counteract peripheral insulin resistance, active atrial contraction to offset impaired left ventricular filling during diastole due to myocardial fibrosis and stiffening, recruitment of supplementary neural circuits in prefrontal brain regions to maintain cognitive performance in the face of neural structural–functional changes (Thomas et al. 2002; Chang & Halter, 2003; Reuter‐Lorenz & Park, 2014). At some point, however, these compensatory modifications become exhausted or overwhelmed, and the effects of physiological ageing become manifest, even pathophysiological, increasing our risk of functional limitations and chronic disease (Epel & Lithgow, 2014). Moreover, these mechanisms of ageing are highly interconnected. For example, oxidative stress and inflammation are mutually reinforcing processes that can be sustained by any number of the above stimuli including dysfunctional mitochondria, cellular senescence, impaired autophagy, macromolecular damage and adverse epigenetic events (Rubinsztein et al. 2011; Cencioni et al. 2013). Mitochondrial dysfunction is directly linked to impaired autophagy (‘mitophagy’), intracellular energy sensing pathways are tightly coupled to stress resistance, and so on (Green et al. 2011; Salminen & Kaarniranta, 2012). On the positive side, each of these mechanisms can, in theory, be manipulated, and numerous laboratories worldwide are engaged in such efforts (Hadley et al. 2005; Vijg & Campisi, 2008; Rae et al. 2010; Kirkland, 2013; Lopez‐Otin et al. 2013; de Cabo et al. 2014; Seals et al. 2014 a; see below).

The particulars of these mechanisms aside, observations from both preclinical and clinical investigations support the possibility that lifespan and, potentially, healthspan can be modified (Fontana et al. 2014; Seals & Melov, 2014 a). Basic research on model organisms of ageing has shown repeatedly that genetic and, more recently, pharmacological manipulation of specific molecular pathways (e.g. inhibition of mTOR signalling) can extend lifespan in both invertebrates and mice (Harrison et al. 2009; Neff et al. 2013). Moreover, there is some evidence that modification of these pathways may improve healthspan (Flynn et al. 2013; Zhang et al. 2014), although much more evidence is needed to support that possibility (Neff et al. 2013; Seals & Melov, 2014 a,b).

Evidence in humans is consistent with these findings in animal models. For example, centenarians, including those clustered in so‐called ‘blue zones’ throughout the world (i.e. areas with unusually high numbers of long‐lived people), not only demonstrate exceptional longevity, but often remain disease‐ and disability‐free until very late in life (Hitt et al. 1999; Willcox et al. 2008; Engberg et al. 2009). California Seventh‐Day Adventists, many of who follow strict healthy lifestyle practices, appear to exhibit both extended healthspan and greater life expectancy than peers from various control populations (Beeson et al. 1989; Fraser & Shavlik, 2001). Indeed, the pioneering work of Lester Breslow on the population of Alameda County, CA, demonstrated that adults who engage in healthy lifestyle practices live longer and with less disability (Breslow & Enstrom, 1980; Breslow & Breslow, 1993). Collectively, these observations suggest that some degree of optimal longevity is probably achievable.

‘Rectangularization’ of physiological function with ageing

Given that declines in physiological function with ageing are a major obstacle to increasing healthspan, and that extending healthspan appears biologically plausible, it follows that delaying, minimizing or, in some cases, preventing age‐associated impairments in physiological function is also attainable and should be a major goal of future biomedical research. Specifically, maintaining physiological function with ageing would have the effect of delaying chronic diseases and disability to a later age of onset, which would extend healthspan, compress morbidity, increase mean life expectancy, and, ultimately, help achieve optimal longevity (Seals & Melov, 2014 a). So, as with the issue of morbidity, a key question is whether it's possible to ‘compress’ physiological dysfunction (or at least severe dysfunction) to a shorter period later in life (Seals & Melov, 2014 a).

Alternatively (and, perhaps, more positively), can physiological function be ‘rectangularized’, such that it remains relatively well preserved until near the end of life? In this context, the accelerated decline in function that occurs at some point near the end of the normal ageing process can be viewed as eventually reaching a threshold below which functional limitations and increased risk of disease and disability occur, thus determining the healthspan of that individual or group (Fig. 4 A). The rectangularization of function with ageing would delay the age at which the threshold is reached, thereby increasing healthspan (Fig. 4 B). Whichever perspective one choses, it is clear that to fully optimize healthspan and longevity, we must optimize physiological function throughout the lifespan, including physical and cognitive function (Beard & Bloom, 2014; Seals & Melov, 2014 a).

Figure 4. Optimization of function with ageing is required for increased healthspan .

A, physiological function declines with ageing, and the portion of life during which function remains above the disease/morbidity threshold represents healthspan. B, to increase healthspan, it is necessary to compress severe dysfunction to a period later in life, effectively ‘rectangularizing’ function as much as possible throughout the lifespan.

Some optimization of function with ageing seems possible for all adults (population‐based optimization), although how well function can be maintained within an individual over time will be influenced strongly by environmental and, perhaps, genetic factors. Substantial variability in the declines in function among individuals is a well‐recognized feature of physiological ageing in humans (Crimmins et al. 1996; Lowsky et al. 2014) and, although not as well documented experimentally, is also likely in other species (Seals & Melov, 2014 a,b). Understanding the determinants of inter‐individual variability in functional changes with ageing and establishing effective strategies to enhance function at the population level are among the research priorities moving forward.

Strategies for preserving physiological function with ageing

Lifestyle–behavioural and pharmacological strategies are the major candidate interventions for preserving physiological function with ageing. An ideal strategy or intervention would be effective in one or both of the following settings.

Primary prevention

The most effective strategies would delay (to a later age of onset), reduce in magnitude, and/or prevent the age‐associated decline of the function in question (primary prevention of dysfunction; Fig. 5). This would, in turn, minimize age‐related decreases in functional status and the associated negative downstream sequelae, thus contributing to an increase in healthspan. Such strategies might exert their beneficial effects by slowing or preventing the upstream biological events that lead to the loss in function with ageing in the first place. This could be viewed as ‘primordial’ prevention, as has been used in the context of preventing the development of conventional risk factors for CVD (Weintraub et al. 2011).

Figure 5. Strategies for preserving physiological function with ageing: primary and secondary prevention .

Lifestyle–behavioural and pharmacological strategies have the potential to delay, reduce or prevent age‐related dysfunction (primary prevention) and/or to improve function in older adults with existing dysfunction to prevent disease and disability (secondary prevention).

Returning to the earlier examples of functional declines with ageing, an effective primary prevention strategy might preserve muscle strength with ageing by minimizing motor unit loss/reorganization, enhancing muscle activation strategies or maintaining muscle mass; vascular function might be maintained by preserving nitric oxide (NO) bioavailability; diastolic heart function might be preserved by preventing age‐related cardiac fibrosis; and renal function might be sustained by maintaining glomerular structural integrity. In any case, strategies that target primary prevention of age‐associated dysfunction are likely to have the greatest potential to extend healthspan. However, the nature of primary prevention is such that strategies will be most effective when applied over the course of life or, at the least, from early adulthood onwards. Unfortunately, this influence also increases the challenge of sustaining subject adherence (compliance) to the strategy over decades (Kirkland, 2013), as many interventions involve short‐lived adaptations that require regular reinforcement of a change in signalling or an adaptation to stress (hormesis).

Secondary prevention

In addition to primary prevention, an effective strategy (intervention) would improve function in middle‐aged and older adults in whom some degree of physiological dysfunction already has occurred, with the objective of delaying or possibly preventing the transition to functional limitations, clinical geriatric syndromes (e.g. frailty), chronic disease and/or medical disability (i.e. secondary prevention) (Fig. 5). In this setting, such strategies could be considered ‘treatments’ or ‘therapies’ for existing age‐associated impairments in function. As with primary prevention, strategies for secondary prevention of functional limitations, disease and disability with ageing would likely target the causal structural changes and/or other biological determinants of the functional decline (Fig. 3). Unlike primary prevention, however, interventions for secondary prevention must have the ability to improve function (or at least slow further declines) in middle‐aged/older adults with baseline dysfunction – i.e. the strategy must have efficacy as a later‐life intervention (Rae et al. 2010; Carter et al. 2012; Seals, 2014; Seals & Melov, 2014 a).

A comprehensive review of potential primary and secondary prevention strategies for maintaining physiological function with ageing is beyond the scope of this review, but a limited discussion of some of the more promising approaches with possible broad systemic effects is presented below. Recent discussions of cognitive interventions with ageing are available elsewhere (Daffner, 2010; Reijnders et al. 2013; Bamidis et al. 2014).

Lifestyle–behavioural strategies

Lifestyle–behavioural strategies to promote preservation of physiological function with ageing include physical activity, healthy dietary practices, cognitive stimulation paradigms, and conventional preventive medicine practices, such as not smoking and regular checkups. With regard to effects on multiple physiological functions, much of the available data relates to the potential modulating influences of physical activity and diet.

Regular physical activity

Regular physical activity is perhaps the lifestyle–behavioural strategy for which there is the strongest overall evidence of function‐preserving effects with ageing. In general, greater occupational and recreational physical activity, as well as higher levels of regular structured physical exercise, has been linked to better preservation of function with advancing age (Tanaka & Seals, 2008; Booth & Zwetsloot, 2010; Booth et al. 2011). The effects of physical activity are consistent among widely differing research models of ageing, including preclinical investigations performed in rodents, cross‐sectional analyses of physically active vs. sedentary adults, longitudinal observational studies associating physical activity levels with functional declines, and prospective exercise intervention trials performed on late middle‐aged/older subjects (Tanaka & Seals, 2008; Vogel et al. 2009; Booth & Zwetsloot, 2010; Booth et al. 2011; Seals, 2014). The evidence supports the ability of regular physical activity to either lessen or prevent physiological decline with ageing, and also supports the efficacy of increases in physical activity for improving function as a later‐life intervention in older adults.

Numerous physiological functions that decline with ageing (e.g. cardiorespiratory fitness and glucose–insulin regulation, neuromuscular, cardiac, vascular and cognitive function) remain at higher levels at any particular age in adults who are chronically physically active compared with their sedentary peers (Tanaka & Seals, 2008; Vogel et al. 2009; Booth & Zwetsloot, 2010; Booth et al. 2011; Seals, 2014). Given that changes in motor performance with ageing predict future morbidity and mortality, it is notable that higher physical activity levels are associated with reduced rates of age‐associated declines in several such neuromuscular functions (walking distance, stair climbing, gait speed and activities of daily living), as well as medical disability (Buchman et al. 2007; Chakravarty, 2008; Paterson & Warburton, 2010; Chang et al. 2013; Pahor et al. 2014). There appears to be a dose–response relation to these effects, and, importantly, evidence suggests that increasing physical activity later in life after being inactive as a young adult can restore the same low‐risk profile as older adults who have been continuously active (Paterson & Warburton, 2010). The accumulating experimental support for favourable effects of regular physical activity on cognitive function, brain repair and inhibition of neurodegeneration with ageing, a major health concern of older adults, is particularly compelling (Colcombe & Kramer, 2003; Studenski et al. 2006; Geda et al. 2010).

Absolute differences and patterns of decline in specific physiological functions with ageing in physically active vs. sedentary adults have been reviewed elsewhere (Tanaka & Seals, 2008; Booth & Zwetsloot, 2010; Booth et al. 2011; Seals, 2014). In short, data from cross‐sectional analyses indicate that the age at which decreases in key functions such as cardiorespiratory fitness and muscle strength reach levels associated with frailty can be delayed by up to 30 years in exercise‐trained compared with inactive healthy adults (Booth & Zwetsloot, 2010). These results are supported by findings of an ongoing longitudinal study showing striking postponement in the development of disabilities and increased survival with advancing age in a population of runners compared with healthy community controls (Chakravarty, 2008). Epidemiological analyses indicate that even moderate levels of physical activity (e.g. only half of the presently recommended 150 min week⁻¹) have a significant impact on life expectancy (Lee & Paffenbarger, 2000; Moore et al. 2012). Recent findings from a multicentre randomized clinical trial also show that a programme of moderate exercise can reduce incident (future) mobility‐based disability in older adults with functional limitations at baseline (Pahor et al. 2014). Collectively, these observations provide strong evidence for the ability of regular physical activity to preserve function, compress morbidity and disability, extend lifespan and contribute to optimal longevity.

The cellular and molecular mechanisms underlying the benefits of regular physical activity on physiological function with ageing are incompletely understood, but probably involve slowing or reversing one or more of the fundamental mechanisms of ageing described above (Booth & Laye, 2009; Fiuza‐Luces et al. 2013; Seals, 2014; Fig. 6). The specific adaptations induced and associated mechanisms are influenced by the type and other characteristics of the physical activity performed. In general, regular aerobic exercise is associated with increased NO bioavailability and reduced oxidative stress and chronic low‐grade inflammation in older rodents and humans (Gleeson et al. 2011; Seals, 2014). Regular exercise suppresses oxidative stress by preventing or reversing age‐associated increases in superoxide production from several sources including the major oxidant enzyme NADPH oxidase, dysfunctional mitochondria, and uncoupled endothelial NO synthase (Seals, 2014; Seals et al. 2014 a). The lowered superoxide concentrations with chronic exercise, in turn, reduce superoxide reaction with NO, thus increasing NO bioavailability (Seals, 2014). Exercise also mitigates age‐related oxidative stress by stimulating antioxidant enzyme defenses, and inhibits inflammation in part by suppressing activation of the master pro‐inflammatory transcription factor, nuclear‐factor kappa B (Pierce et al. 2011; Seals et al. 2014 b; Seals, 2014; Walker et al. 2014).

Figure 6. Lifestyle–behavioural strategies that increase function and potential underlying mechanisms .

Regular physical activity, restricted energy intake and healthy diet composition enhance physiological function and healthspan, promoting optimal longevity. The molecular/biological mechanisms underlying these benefits may involve inhibiting or reversing several fundamental processes of ageing.

Regular exercise also enhances mitochondrial ‘health’ and function, possibly as a result of intermittent activation of energy‐sensing pathways, and this is associated with increased capacity for oxidative metabolism (McArdle et al. 2002; Lanza & Nair, 2009). An upregulation of stress resistance pathways is also observed with exercise, including autophagy/mitophagy and heat shock proteins (He et al. 2012; Fittipaldi et al. 2014), although this has not been studied in the context of ageing. Prevention of the effects of genome instability, maintenance of telomere length and telomerase, improved protein homeostasis, enhanced stem cell bioavailability/function, epigenetic alterations, and release of signalling molecules from active skeletal muscle are among the other mechanisms believed to contribute (Kaliman et al. 2011; Simpson et al. 2012; Fiuza‐Luces et al. 2013). Improvements in cognitive function with regular physical activity have been linked in part to neuronal growth (neurogenesis) associated with increases in growth factors such as brain‐derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin‐like growth factor (IGF) (Voss et al. 2013; Lee et al. 2014). Much remains to be determined about the mechanisms by which regular exercise preserves physiological function with ageing.

Diet

Restricted energy intake

The influence of reductions in energy intake on longevity and physiological function with ageing has been reviewed in detail recently (Cava & Fontana, 2013; de Cabo et al. 2014; Rizza et al. 2014). Much of what has been reported comes from studies of chronic caloric restriction (with maintained nutrient intake) in rodents. Lifelong dietary restriction up to 40% of ad libitum feeding increases lifespan in several, although not all, strains of mice and rats, and possibly non‐human primates (Cava & Fontana, 2013; de Cabo et al. 2014; Rizza et al. 2014). Lifelong calorie restriction also reduces or prevents several types of physiological declines with ageing in rodents, including vascular endothelial dysfunction, stiffening of the large elastic arteries, elevations in systolic blood pressure, cardiac diastolic dysfunction, hepatic insulin and lipid dysregulation, neuromuscular dysfunction and impairments in cognitive function and memory (Bowman et al. 2010; Weiss & Fontana, 2011; Arum et al. 2013; Cava & Fontana, 2013; Donato et al. 2013; Kuhla et al. 2013; de Cabo et al. 2014; Rizza et al. 2014). The mechanisms responsible for the function‐preserving effects of energy restriction with ageing remain under investigation, but are believed to involve sustained activation of pro‐catabolic/anti‐growth energy‐sensing pathways and upregulation of stress resistance systems linked to suppression of chronic low‐grade inflammation, oxidative stress and tissue fibrosis (Chung et al. 2009; Weiss & Fontana, 2011; de Cabo et al. 2014; Rizza et al. 2014; Fig. 6). Short‐term calorie restriction in older animals appears to induce many of the same effects as lifelong dietary restriction (Rippe et al. 2010; Robertson & Mitchell, 2013).

Relatively few studies have been performed in which energy intake alone has been reduced in late‐middle aged and older humans (e.g. without concomitant exercise training). This is probably due in part to the controversy related to reducing caloric intake and nutrients to older adults in whom total energy and essential nutrient intake might already be compromised, and who may be at risk of (or already demonstrate) sarcopenia and functional limitations (Fontana & Hu, 2014). There are also concerns based on epidemiological findings in older humans and preclinical data in rodents suggesting that somewhat higher body weight and/or adiposity is associated with a survival benefit (Losonczy et al. 1995; Flodin et al. 2000; Breeze et al. 2006). Findings from weight loss intervention studies that have been performed on healthy normal weight‐to‐obese middle‐aged/older humans have reported improvements in vascular function, glucose–insulin regulation, memory and mobility (Pierce et al. 2008; Villareal et al. 2008, 2011; Witte et al. 2009). These results are consistent with observations of preserved cardiac diastolic, vascular, autonomic nervous system and glucose–insulin function, and lower markers of inflammation in middle‐aged/older adults who engage in chronic self‐imposed caloric restriction (Weiss & Fontana, 2011; Stein et al. 2012; Rizza et al. 2014). Dietary protein restriction and several paradigms involving intermittent fasting (fasting for periods during the week or day) have also been advanced for attenuating functional declines or enhancing health with ageing (de Cabo et al. 2014; Longo & Mattson, 2014; Rizza et al. 2014). However, as with any form of dietary restriction, safeguards would be needed to ensure adequate nutrition, especially when applied to older adult populations.

Diet composition

Findings from preclinical investiga‐tions, as well as cross‐sectional, longitudinal (observa‐tional) and intervention studies in humans support a significant modulatory effect of diet composition on changes in physiological function with ageing. In general, there is growing evidence that diets that are high in fruits and vegetables, whole grains, fish, nuts and vegetable oils, including well‐established ‘holistic’ healthy diets such as the DASH (Dietary Approaches to Stop Hypertension), Mediterranean and Portfolio diets, may exert function‐enhancing effects with ageing (Jenkins et al. 2008; Mozaffarian et al. 2011; Rizza et al. 2014; Seals et al. 2014 a). Consumption of these diets is associated with positive functional and overall health profiles with ageing, including better maintenance of motor, vascular, cognitive, renal and immune function (Solfrizzi et al. 2006; Mozaffarian et al. 2011; Gibson et al. 2012; Chrysohoou et al. 2013; Gopinath et al. 2013; Seals et al. 2014 a). Given these observations, there has been considerable interest in determining if similar benefits are associated with specific components or ingredients of these diets. In support of this concept, higher dietary intake of several constituents of these broader dietary patterns including fish, vegetable (e.g. olive) oils, berries, spinach, grape products and other polyphenols, nuts (walnuts), coffee, green tea and lower‐fat dairy products, as well as lower sodium intake, have been reported to be positively related to physiological function with ageing in observational studies and/or in intervention trials involving middle‐aged/older rodents and humans (Joseph et al. 1999; Shukitt‐Hale et al. 2009; Baeza et al. 2010; Mozaffarian et al. 2011; Seals et al. 2014 a).

Pharmacological and other interventions

Several pharmacological and other strategies either exist or are currently in development that could be explored for potential function‐enhancing effects with ageing. Whether these approaches can exert the broad systemic effects of physical activity, healthy diet and, perhaps, other lifestyle behaviours remains to be determined. However, by restoring the expression or bioavailability of essential molecules and the normal activity of vital signalling pathways, these interventions could contribute to the maintenance of specific functions and might help delay the development of functional limitations, disability and diseases with ageing. In this sense, such strategies could be viewed as ‘complementary’ to healthy behaviours and worthy of investigation given the historically low population‐wide compliance to positive lifestyle practices (Seals & Melov, 2014 a). Interestingly, many pharmacological compounds currently being promoted or under development are designed with the intent of ‘mimicking’ the effects of exercise and healthy diet on signalling networks involved in regulation of physiological function (Booth & Laye, 2009; Bamman et al. 2014; Seals et al. 2014 a; Fig. 7). One concern with this approach is the possibility of negative interactions between specific agents and healthy lifestyle behaviours, perhaps due to activation/inhibition of the same signalling pathways (Wray et al. 2009; Gliemann et al. 2013; Mikus et al. 2013; Paulsen et al. 2014).

Figure 7. Pharmacological compounds designed to activate signalling pathways of exercise and healthy diet .

Certain prescription drugs and nutraceuticals may have some potential to enhance physiological function with ageing by targeting the same signalling networks that exercise and healthy diet modulate, and/or by suppressing key processes of ageing.

New and existing prescription drugs

Given the need to extend healthspan and compress morbidity in our rapidly ageing populations, there is considerable interest in developing new prescription medications for treating clinical conditions/syndromes of ageing such as sarcopenia and frailty, cognitive dysfunction, and other age‐associated disorders (Kirkland, 2013; Stipp, 2013; Fontana et al. 2014; Seals et al. 2014 a; Seals & Melov, 2014 a). Many drugs and alternative therapies presently are under development that would target the putative mechanisms of ageing described above (Kirkland, 2013; Lopez‐Otin et al. 2013; de Cabo et al. 2014). These include agents that act to restore mitochondrial health, regulate senescent cells, suppress growth‐promoting pathways, activate energy‐mobilizing networks, inhibit inflammation, activate autophagy, enhance proteostasis, modulate gene transcription (e.g. epigenetic modulators), activate telomerase and boost nitric oxide, as well as stem cell‐related therapies. On the basis of extensive findings in preclinical models showing increases in lifespan and, to a lesser extent, maintenance of age‐associated function, currently there is intense research and commercial interest in the inhibitor of mTOR, rapamycin, and its related analogues (so‐called ‘rapalogs’) (Blagosklonny, 2012). Overall, the pathway for development of new ‘anti‐ageing’ agents is daunting and expensive (Kirkland, 2013), but the great anticipated demand is expected to continue to drive activity in both academic and industry settings (Seals & Melov, 2014 a).

Another option is represented by existing prescription agents already approved by regulatory agencies (Seals et al. 2014 a; Seals & Melov, 2014 a). Examples would include statins, renin–angiotensin–aldosterone system inhibitors, newer generation β‐adrenergic receptor inhibitors, thiazolidinediones, metformin and anti‐inflammatory medications. These drugs are commonly used in the treatment of patients with chronic medical disorders and have established efficacy and safety in those clinical populations. Many such agents have been shown to enhance or preserve physiological function in middle‐aged/older patients with chronic disease (Onder et al. 2002; De Jager et al. 2005; Seals et al. 2014 a). These drugs presently are not ‘indicated’ for treating age‐associated physiological dysfunction, functional limitations, disorders (sarcopenia, frailty) or the underlying mechanisms (e.g. inflammation) in the absence of clinical disease. However, these agents could, theoretically, be ‘repurposed’ for preventing or treating specific conditions or syndromes of ageing created by severe physiological impairments (Seals & Melov, 2014 a). To do so would probably involve new clinical trials with regulatory authority‐approved endpoints, potentially long treatment durations, and large sample sizes, depending on the expected incidence of the endpoint(s) under study. Such drugs could also be prescribed at present to older adults for potential ‘off‐target’ effects in combating physiological dysregulation and related states of ageing, should existing or new clinical evidence suggest clear benefit for a particular patient or group. Some non‐prescription drugs, such as non‐steroidal anti‐inflammatories (NSAIDS), may also exert function‐modulating effects with ageing (Landi et al. 2013). Finally, it may be possible to design a cost‐effective, function‐enhancing ‘polypill’ consisting of low doses of some combination of the approved clinical agents mentioned above, as has been advanced for secondary prevention of cardio‐metabolic diseases (Lonn et al. 2010; Castellano et al. 2014).

Nutraceuticals

Although definitions vary, nutraceuticals can be considered as foods or natural ingredients within foods with potential health benefits beyond their basic nutritional value (Wrick, 2005; El Sohaimy, 2012). This category of pharmacological agents can include dietary supplements, functional foods and medical foods. Most products within this class are not under direct regulatory oversight and are sold ‘over the counter’ in retail stores or directly to the consumer. Because nutraceuticals are generally less expensive to develop and market, presently there is strong interest in this broad category of pharmacological compounds as potential anti‐ageing agents (Nadon et al. 2008; Imai, 2010; Seals et al. 2014 a; Seals & Melov, 2014 a). Many of these compounds target the same signalling pathways as positive lifestyle behaviours, although, as with pharmaceuticals, there is skepticism as to whether any nutraceutical can produce the same broad physiological benefits as exercise or other healthy lifestyle behaviours (Booth & Laye, 2009; Mozaffarian & Wu, 2011; Bamman et al. 2014; Seals et al. 2014 a). Other concerns with nutraceuticals include an absence of evidence supporting efficacy and differences in formulations among brands (Seals & Melov, 2014 a).

One of the most well characterized nutraceuticals for its possible effects on physiological function with ageing is resveratrol, a polyphenol found in red wine and grapes. Resveratrol activates sirtuin‐1 (SIRT‐1), a nicotinamide adenine dinucleotide (NAD)‐dependent protein deacetylase and ADP‐ribosyltransferase that is part of the cellular energy sensing and stress resistance network. Activation of SIRT‐1 with resveratrol and other agonist compounds has been reported to inhibit several aspects of cellular ageing (Price et al. 2012; Imai & Yoshino, 2013). Results from both preclinical and clinical research studies suggest that supplementation with resveratrol may improve age‐associated neuromuscular performance (e.g. strength and endurance), glucose–insulin metabolism, vascular function and other physiological biomarkers with ageing (Marchal et al. 2013; Tome‐Carneiro et al. 2013; de Cabo et al. 2014). Resveratrol may induce these effects through a variety of SIRT‐1‐dependent or ‐independent mechanisms, including antioxidant, anti‐inflammatory and/or nitric oxide‐enhancing actions, as well as cytoprotective effects mediated via stimulation of cellular stress resistance pathways (Knutson & Leeuwenburgh, 2008; Kulkarni & Canto, 2014). Clinical trials are presently being conducted to assess possible benefits in larger groups of middle‐aged and older adults. Recent reports suggest that resveratrol supplementation may inhibit some of the potential physiological benefits of exercise (Gliemann et al. 2013; Scribbans et al. 2014), indicating that additional studies assessing interactions between this compound and lifestyle interventions are needed.

In addition to resveratrol, there is also evidence that supplementation with omega‐3 fatty acids may improve function, particularly cardio‐metabolic health, with ageing (Kalmijn et al. 2004; Mozaffarian & Wu, 2011). NO‐enhancing strategies involving either pharmacological supplementation with inorganic nitrates or nitrites, or dietary interventions associated with increased consumption of nitrate‐rich functional foods (e.g. beetroot juice) are also being pursued (Leiter et al. 2012; Kelly et al. 2013; Sindler et al. 2014). Other examples of nutraceuticals currently under study for their potential function‐enhancing effects with ageing include NAD⁺‐boosting compounds that activate SIRT‐1 (Imai, 2010; Imai & Yoshino, 2013), autophagy‐stimulating agents (e.g. spermidine, trehalose; LaRocca et al. 2012, 2013; Gupta et al. 2013), compounds with anti‐inflammatory actions (e.g. curcumin; Frautschy et al. 2001; Fleenor et al. 2013) and vitamin D (especially for vitamin D insufficient/deficient older adults; Verhaar et al. 2000; Bischoff‐Ferrari et al. 2004).

There is little evidence that commonly used antioxidant supplements (vitamin C, vitamin E, etc.) improve function with ageing, and some reports actually suggest possible negative effects with chronic adminis‐tration (Kris‐Etherton et al. 2004). However, other antioxidant‐acting/enhancing compounds demonstrate promise. For example, the superoxide‐scavenging compound TEMPOL and the mitochondrial‐specific antioxidant MitoQ recently have been shown to reverse vascular dysfunction with ageing in mice (Fleenor et al. 2012; Gioscia‐Ryan et al. 2014). Moreover, there continues to be strong interest in agents that can stimulate endogenous enzymatic antioxidant pathways (e.g. superoxide dismutase) and other stress resistance systems controlled by erythroid 2‐related factor 2 (Nrf2) signalling (Cardozo et al. 2013).

Future directions

The central importance of maintaining optimal function throughout the lifespan will create unprecedented demand for expertise in physiology as we move through the present decades‐long period of rapid population ageing. To fully capture these opportunities and maximize our contributions to societal‐wide efforts to increase healthspan, a greater emphasis on ageing within the field will be required. This new area of physiological geroscience must seek greater knowledge on several topics currently in need of further investigation. Among the key issues to be addressed is determining the temporal patterns of functional declines over the lifespan and the underlying biological mechanisms responsible for those declines. Insight into the former will help determine when we should intervene, whereas the latter will serve to identify cellular and molecular targets for the interventions.

Genetic vs. environmental modulation of function with ageing

Determining the respective influences of genetic and environmental factors will be important in understanding the mechanisms of reductions in physiological function with ageing. This may be particularly challenging for genetic factors. For example, the distinctive phenotype of longevity in centenarians has a significant (25–35%) hereditary component (Sebastiani et al. 2012; Brooks‐Wilson, 2013). However, few gene variants associated with longevity have been identified in this group (APOE, FOXO3A), suggesting that longevity is a polygenetic trait influenced by complex genetic interactions (Shadyab & LaCroix, 2014). The ability to maintain good physiological function and healthspan with ageing may also be influenced by our genome. If so, identifying gene variants, expression patterns and the related molecular regulatory processes (micro RNAs, epigenetic, etc.) associated with preservation of function and healthspan will be a key objective of future efforts.

On the other hand, Seventh Day Adventists and other groups that engage in healthy lifestyle practices also demonstrate increased mean survival and well‐preserved physiological function with ageing, providing compelling evidence that environmental factors play a critical role in healthspan. Indeed, adults engaged in unhealthy lifestyle behaviours (smoking) and those exposed to negative socio‐economic influences such as low education and income status tend to undergo accelerated rates of functional declines with ageing (Fried & Guralnik, 1997; Koukouli et al. 2002; Turrell et al. 2007; Sabia et al. 2008). Greater insight is needed regarding these and other social demographic and psychological influences on physiological function with ageing. For example, women have greater rates of disability with ageing than men (Leveille et al. 2000), and must adapt physiologically to both advancing age and oestrogen deficiency during and after menopause. As such, it will be important in future preclinical and clinical studies to determine sex differences in functional declines with ageing. Similarly, rates of disability and other health outcomes with ageing are influenced by race–ethnicity status (Banks et al. 2006; Warner & Brown, 2011), suggesting that this factor is also a potentially important determinant of age‐associated functional declines. Moreover, emerging evidence suggests that one's psycho‐emotional state, including optimism, resilience, purpose in life and depressive symptoms, also affects physical‐cognitive function and risk of frailty and chronic diseases with ageing (Ostir et al. 2004; Fredman et al. 2006; Inzitari et al. 2006; Steptoe et al. 2006; Lamond et al. 2008).

The biological mechanisms linking these socio‐demographic and psychological factors to impaired physiological function and consequent morbidity with ageing have not been systemically studied, but presumably involve modulation of the fundamental mechanisms of ageing described above (Fig. 8 A). The specific signalling pathways by which these interactions would occur are unknown, but new theories of social regulation of gene expression represent one possible mechanistic process (Cole, 2013; Epel & Lithgow, 2014). The general concept is that ‘social programmes’ have evolved to better link our changing psycho‐social environment to biological processes that allow us to adapt physiologically to new challenges and stress (Cole, 2013; Epel & Lithgow, 2014). It is postulated that psycho‐social stimuli are sensed by the central nervous system, which signals targeted cells/tissues using the peripheral nervous and/or endocrine systems to alter gene transcription and protein translation to influence physiological function and behaviour (Fig. 8 B). Common events with advancing age such as personal loss, social isolation, depression and other life transition‐related stress may be sensed and activate or inhibit transcriptional programs (e.g. pro‐inflammatory networks) that could favourably (adaptive) or unfavourably (maladaptive) modulate physiological function. Such influences may play an important role in determining inter‐individual differences in age‐related functional declines, with net positive (function‐preserving) or negative (function‐reducing) effects during a particular phase of life. It is also possible that other environmental (e.g. healthy lifestyle behaviours) or genetic (e.g. gene variants) factors influence responsiveness to a particular psycho‐social stimulus among individuals, rendering some adults more or less ‘sensitive’ to (or protected from) these putative stressors.

Figure 8. The influence of social demographic and psychological factors on physiological function with ageing .

A, social influences and psycho‐emotional traits may affect physiological function and disease risk with ageing by modulating the fundamental biological mechanisms of ageing. B, these factors may exert their effects in part by stimulating the central nervous system and thereby altering peripheral signalling that influences gene transcription and cellular function.

Optimizing function with ageing: strategies, implementation and costs

The ultimate goal of future efforts in physiological geroscience must be to establish effective strategies for optimizing physiological function throughout the lifespan. Although the focus here is on preserving function at its highest possible levels with advancing age, it is important to recognize that maximizing function in childhood and maintaining high function coming into middle‐age/older adulthood based on proper physical activity and other healthy lifestyle behaviours will play a key role in determining physiological status later in life. In any case, much more insight is needed on several issues related to strategies for enhancing function with ageing, including the examples listed in the Table 1. These and other critical issues on this topic can be most effectively addressed using a translational physiology‐based research approach that includes investigators working from the molecular to population physiology levels, as emphasized recently (Seals, 2013; Seals et al. 2014 a, b; Seals & Melov, 2014 a).

Table 1.

Strategies for optimizing physiological function with ageing: outstanding issues

One of the greatest challenges for increasing healthspan may be our ability to achieve widespread voluntary implementation of healthy ageing strategies at the community level. Success in unravelling the complex mechanisms underlying age‐related declines in physiological function, identifying effective interventions, and establishing new clinical guidelines and public health policies will have limited impact if we cannot, in parallel, develop effective approaches for adopting behavioural changes and maintaining compliance to other function‐preserving strategies. A major concern in this context would be adherence to newly developed healthy ageing approaches only in selective populations, such as higher education and income groups. A scenario could be envisioned in which compression of morbidity occurs in the wealthiest, most educated adults, with concomitant expansion of morbidity (longer life, but greater dysfunction, disease and disability) in the poor and less educated (Chatterji et al. 2014). Existing disparities in disease risk, diet, physical activity and other metrics of health and wellness based on socio‐economic status make this an all‐too‐real possibility (Pampel et al. 2010).

In addition to effective implementation efforts, it will be important for colleagues in health care economics, social demography, public policy and related fields to continue to assess the socio‐economic impact of successful efforts to increase healthspan. The economic value of delaying ageing and increasing healthspan in the USA recently was estimated at ∼$7 trillion dollars over the next 50 years (Goldman et al. 2013). However, even modest increases in life expectancy associated with enhanced healthspan would significantly increase entitlement outlays, which would, in turn, require changes to the eligibility age for such programmes to offset the increased costs (Goldman & Olshansky, 2013; Harper, 2014). Clearly, it will be important to consider all aspects of new initiatives focused on extending healthy function and lifespan. That said, the risk of standing pat and not addressing key issues related to rapid population ageing and healthspan, including the need to optimize physiological function and quality of life, is probably an even more dangerous, burdensome and unsustainable alternative (Goldman & Olshansky, 2013; Beard & Bloom, 2014; Harper, 2014).

Physiological geroscience: an integrative model and new initiative

Overall, physiological geroscience can be viewed as a new initiative that leverages interdisciplinary expertise from many complementary fields to address the major challenges in the physiology of ageing (Fig. 9). These challenges include a better understanding of the types and temporal patterns of declines in physiological function with ageing, identifying the underlying biological mechanisms and modulatory influences of functional impairments, establishing the efficacy of prevention and treatment strategies, and implementation of clinical guidelines and population health policies, all aimed at establishing a set of ‘best practices’ for optimizing function throughout the lifespan. These guidelines would be based in part on lifestyle and pharmacological approaches that favourably alter the balance of the fundamental mechanisms by which ageing influences physiological function (Fig. 9).

Figure 9. Physiological geroscience: a translational approach for optimizing physiological function with ageing .

Cross‐disciplinary efforts aimed at assessing physiological dysfunction with ageing, identifying the underlying mechanisms, and establishing the efficacy of prevention/treatment strategies, have the potential to impact public health by informing clinical guidelines and promoting evidence‐based ‘best practices’ for healthy ageing.

Based on this multidisciplinary translational model, we must initiate new coordinated efforts to emphasize the importance of physiological function in healthspan, and to establish the necessary research models, programmes and resources to pursue a robust research agenda for promoting functional vitality with ageing (Seals & Melov, 2014 a). Specific activities would include translational symposia, workshops and meetings that identify key research priorities; new funding mechanisms for both independent and collaborative research; increasing the infrastructure for assessing physiological function in animal models (e.g. phenotyping cores) and humans with ageing and interventions; and establishing career development opportunities emphasizing the translational study of physiological function with ageing (Kirkland & Peterson, 2009; Seals, 2013; Seals & Melov, 2014 a,b).

Matching research opportunities in this field with the necessary forums for scientific interaction and development, resources and workforce availability will be essential to maximize progress. Importantly, with the initial wave of baby boomers already having entered traditional retirement ages and more coming every day, we find ourselves without the planning and infrastructure necessary to meet the healthcare demands and expectations of current and future generations of older adults (Seals & Melov, 2014 a). We are far behind, and presently in a biomedical research funding environment that poses more of an obstacle (certainly a limitation) than a mechanism for catching up.

Conclusions

Physiological function declines with ageing and is a major contributor to age‐associated morbidity, disability and mortality. Accordingly, preserving physiological function with ageing is an essential component of extending healthspan (the period of healthy, productive and independent ageing) and achieving optimal longevity (living long, but in a state of wellness until near the end of life). With rapid worldwide population ageing, our ability to establish effective strategies to maintain physiological function with advancing age will be a major factor in determining the impact of ageing on individuals, their families and society. To be successful, the skills and expertise of investigators working throughout the translational research continuum in physiology and many other disciplines will be needed in this new field of physiological geroscience.

Additional information

Competing interests

None declared.

Funding

The authors are supported by National Institutes of Health awards AG013038, HL107120, AG042795 and AG00079.

Biography

Douglas Seals obtained his PhD from the University of Wisconsin–Madison and performed postdoctoral training at Washington University School of Medicine in St. Louis, MO, USA. His initial faculty position was at the University of Arizona in Tucson. In 1992, he moved to the University of Colorado Boulder, where he is presently a College Professor of Distinction in the Department of Integrative Physiology. His research focuses on the integrative physiology of ageing. For the past decade, his laboratory has used translational experimental approaches to investigate the physiology and pathophysiology of vascular ageing and, more recently, declines in motor function, particularly the underlying mechanisms involved and the efficacy of treatments.