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.

© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Figures

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).

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).

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.

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.

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).

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.

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.

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.

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.