Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity?


Remodelling of the immune system with age — immunosenescence — is a substantial contributor to poor health in older adults, with increasing risk of infections, cancer and chronic inflammatory disease contributing to age-related multi-morbidity. What is seldom considered when examining the immune response of an aged individual is that the immune system is profoundly influenced by physical activity. Habitual physical activity levels decline with age, with significant consequences for muscle mass and function. Skeletal muscle is a major immune regulatory organ and generates a range of proteins, termed myokines, which have anti-inflammatory and immunoprotective effects. Several studies indicate that maintaining physical activity has immune benefits in older adults, for example, it reduces the systemic inflammation associated with chronic age-related diseases. Here, we discuss how physical activity can prevent or ameliorate age-related multi-morbidity by boosting immune function, and we consider whether physical activity could improve immunotherapy outcomes in age-related conditions such as cancer.

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Fig. 1: The evolution of increased longevity.
Fig. 2: Muscle as an immune regulatory organ.
Fig. 3: Physical activity as an immune adjuvant.


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The authors thank M. Whitham and A. Skulas-Ray for their careful reading of the manuscript.

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Nature Reviews Immunology thanks M. Phillips, K. Timmerman and J. Turner for their contribution to the peer review of this work.

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J.M.L., N.A.D., S.D.R.H., R.J.S. and G.N. were all involved in researching the data, discussing the content, and writing, reviewing and editing the manuscript.

Correspondence to Janet M. Lord.

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Healthy life expectancy

Life expectancy is the predicted total number of years an individual is likely to live, and the proportion of life that will be spent in good health is termed the healthy life expectancy or health span.


A condition of low muscle mass and function (strength) that commonly occurs with age or chronic illness. The European Working Group on Sarcopenia in Older People has defined low muscle mass as >2 standard deviations from the mean value for young adults, and low strength as a walking speed of less than 0.8 m s–1 and a hand grip strength of <30 kg in males or <20 kg in females.


The twofold to fourfold increase in systemic levels of inflammatory cytokines (for example, tumour necrosis factor, IL-1β and IL-6) and reduced levels of anti-inflammatory cytokines (for example, IL-10) seen with advanced age. The degree of inflammageing is associated with increased risk of a range of age-related diseases, including cardiovascular disease, osteoporosis, cancer and dementia.

Senescence-associated secretory phenotype

(SASP). Senescent cells are classically proliferatively quiescent but highly active metabolically. They have a rich secretory output termed the SASP, which contains pro-inflammatory cytokines and chemokines, matrix metalloproteinases and growth factors, such as vascular endothelial growth factor. The SASP is thought to be a key mediator of the ageing process.

VO2 max

The maximum rate of oxygen consumption measured during incremental exercise. The value is a measure of an individual’s cardiorespiratory fitness, as it represents the maximum rate at which the heart, lungs and muscles can use oxygen during exercise.

M2-like macrophages

‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as either pro-inflammatory (when ‘classically’ activated with interferon and lipopolysaccharide) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regard to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to describe the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Biological mechanisms driving ageing

In many species, these mechanisms have been proposed to consist of various responses to cell and organelle damage. They include the accumulation of senescent cells, altered nutrient sensing and reduced mitochondrial fitness and stem cell function. Inflammation is one of the key downstream mediators, as senescent cells release pro-inflammatory cytokines.

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