Longevity research should better incorporate the effects of stress on aging, argues professor Elissa Epel of the University of California, San Francisco . She proposes using the concept of stress resilience to capture the differences between beneficial and harmful stress and the multi-level response that mediates the link between stress and aging.
Different types of stress
Epel praises the shift from what she calls the whack-a-mole approach of trying to cure specific diseases to an integrative approach that tries to understand and address biological aging as the underlying cause of these diseases. However, she advocates incorporating stress responses more fully into this model, viewing them as basic mechanisms of aging rather than modifiers.
Her approach includes both physiological stressors that are already part of longevity research, such as hypoxia, and psychological stressors that have received less attention, such as divorce, loss of a job, and caregiving. Epel highlights the importance of interactions between the two types, such as poor mental health affecting recovery from physical stress; she offers the example that depression increases the risk of slow recovery and early mortality in heart disease patients. To some extent, this reflects the fact that stress mediates the link between the social hallmarks and aging.
The paper also discusses the familiar division between chronic stress, which is toxic, and acute stress, which can be beneficial, a process known as hormesis. Epel writes that the cellular biology of hormesis is relatively well characterized, but she wants to expand the concept to include psychological stressors such as “novel challenging experiences that expand coping resources, knowledge, generativity, and feelings of accomplishment.”
Resilience to stress
Epel wants to combine these disparate elements into the concept of stress resilience: the ability of an individual to recover quickly from stressful exposures. She frames the idea to include resilience in three dimensions: physiological, psychological, and social. A person’s ability to cope with stress – and thus its impact on aging – is determined not only by biological stress response but also by that person’s personality, support networks, and related resources.
“Stress resilience, an umbrella term including hormetic stress, can be measured across cellular, physiological, and psychosocial functioning,” said Epel in a press release. “Developing a deeper understanding of stress resilience will lead to more targeted innovative interventions.”
Introducing the concept of stress resilience opens the door to new questions for longevity researchers. For example, how does stress resilience change during development? Aging leads to a decrease in the hormones involved in acute stress response and a decrease in hormesis. The psychological and social dimensions of stress resilience probably also change, which may shift the value of different interventions.
Boosting our capacity
Another benefit is that resilience can serve as a target for interventions. Taking Epel’s view that stress is a basic mechanism of aging, an argument can be made that there is an ideal stress level for longevity. Too much stress leads to accelerated aging, while too little results in the failure to develop buffering resources to cope with stress and an inability to quickly recover.
Stress resilience determines the range of these domains and the size of the Goldilocks zone that results in enhanced functioning, which Epel calls ‘stress rejuvenescence’. Increased stress resilience can help ensure that stress has a beneficial impact on longevity instead of accelerating aging. Interventions that increase our capacity to cope with stress – including social and psychological tools that are already available – could have a significant impact and increase both health- and lifespan.
Geroscience offers a counterpoint to the challenged pursuit of curing diseases of aging, by focusing on slowing the biological aging process for extended healthspan earlier in life. Remarkable progress has led this field toward animal trials and the next challenge lies with translation to humans. There is an emerging number of small human trials that can take advantage of new models integrating behavioral and social factors. Understanding dynamic aging mechanisms, given the powerful social determinants of aging (Crimmins, 2020) and human variability and environmental contexts (Moffitt, 2020), will be critical. Behavioral and social factors are intrinsic to aging. Toxic stressors broadly defined can lead to stress-acceleration of aging, either directly impacting aging processes or by shaping poor behavioral health, and underlie the socioeconomic disparities of aging. In contrast, hormetic stressors, acute intermittent stressors of moderate intensity, can produce stress resilience, the ability for quick recovery and possibly rejuvenation of cells and tissues. Although health research usually examines static biomarkers, aging is reflected in dynamic ability to recover from challenges pointing to new interventions and targets for examining mechanisms. A fuller model incorporating stress resilience provides innovative biobehavioral interventions, both for bolstering response to challenges, such as COVID-19, and for improving healthspan.
Epel’s paper offers a coherent framework for integrating various aspects of stress and stress response into longevity research. She argues that in addition to considering ways to reduce stress, especially chronic stress, scientists should aim to increase stress resilience, as building up this capacity will improve our ability to cope with stress without detrimental aging effects. As Epel wrote in the paper, “models which are focused on pharmacological interventions must expand to be inclusive of both social and behavioral interventions, the current ‘big levers.'”
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 Epel, ES. The geroscience agenda: Toxic stress, hormetic stress, and the rate of aging. Ageing Research Reviews (2020), doi: 10.1016/j.arr.2020.101167
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