Immunosenescence
The term immunosenescence is not restricted to senescence (as a component of biological ageing described earlier) of immune cells but encompasses all immune system modifications that characterise ageing. Components of biological ageing discussed in this chapter are probably synergistic in reducing functions of several physiologic systems, thus contributing to different phenotypes of ageing. Among these physiologic systems, we propose here to emphasise the role of the immune system for two reasons.
First, a major feature of the biology of ageing is chronic low‐grade inflammation (also called inflammageing 61), thought to contribute to age‐related diseases and ageing phenotypes.62 Known causes of this inflammation are other components of biological ageing (mitochondrial dysfunction, cell senescence, loss of proteostasis, epigenetic alterations) and extrinsic factors (chronic infections and changes in microbiota).63 Thus, one could argue that inflammation is more of a bystander consequence than a phenomenon that contributes to ageing. Despite associations between higher levels of inflammatory cytokines, age‐related diseases, and mortality, it is still somewhat unclear how (and even whether) chronic low‐grade inflammation contributes to the ageing process. Nevertheless, ageing mice lacking proteins of the inflammasome pathway exhibit less decline in immune, physical, and cognitive functions than wild‐type mice,64,65 and this pathway is involved in Alzheimer’s disease pathophysiology.66 In addition, if we consider inflammation as a common link between several components of biological ageing and phenotypes of ageing, it becomes an interesting target for intervention. In line with this, drugs specifically designed to block pro‐inflammatory cytokines, such as interleukin‐1β, have reduced the incidence of age‐related diseases in humans.67,68
Second, as the function of the immune system is to maintain homeostasis, it is easy to conceive that defects in this system will exacerbate detrimental effects of other components of biological ageing by failure to eliminate not only pathogens but also pre‐malignant cells, senescent cells, and misfolded proteins. Thus, its contribution to age‐related diseases and ageing phenotypes may be far broader than the usually cited infections, cancers, and auto‐immunity. Both the innate and adaptive arms of the immune system exhibit multiple functional changes with ageing.69 The primary characteristics of the ageing innate immune arm are immune stimulation at the basal level and immune paralysis when specific functions are needed,70 a paradox proposed to constitute the basis of inflammageing. Regarding the adaptive arm, ageing of both B and T cell compartments is mainly characterised by a decreased number of naïve cells able to respond to new challenges and inflation of the pool of memory cells, with shrinkage of their antigenic repertoire.71,72 These changes have been linked to components of biological ageing cited earlier as well as to long‐term exposure to antigens of persistent infective agents, such as cytomegalovirus.73,74
Challenges for the biology of ageing and geriatric medicine
Facing the global challenges of ageing,75 scientists who study this phenomenon have realised there is great urgency to consolidate a body of knowledge that will be helpful in clinical care. The field of geroscience thus emerged,16 followed by perspectives about ‘creating the next generation of translational geroscientists’.76 The geroscience hypothesis is the following: the accumulation of diseases and loss of functions with ageing is driven by common biological mechanisms. Understanding these mechanisms would allow measuring ‘biological age’, predicting adverse outcomes in late life, and ultimately identifying interventions that extend healthspan.
Efforts have been made to identify putative markers of biological ageing27,46,77 but are hampered by (among other things) the lack of a consensual definition of what a biomarker of ageing should measure/predict. Death is obviously a significant outcome but can be preceded by a long period of multimorbidity and disability, so time‐to‐death per se is not a sufficient outcome for a biomarker of healthy ageing. Age‐related multimorbidity is considered because a single disease‐centred approach may focus research on a specific organ or on one limited physiological system. Frailty, conceptually defined as an age‐associated decrease in physiologic reserve, increasing vulnerability to stressors, can be considered a clinical metric of biological ageing.78 There is also growing interest in measuring intrinsic capacity – a composite of all of an individual's physical and mental capacities79 – as a key determinant of functional ability. Markers of biological age described in this chapter are linked to one or several of these outcomes, the multiplicity of which somewhat clouds this area of research. Defining a consensual, relevant set of outcomes should be a first significant step for geroscience.
Therapeutic opportunities targeting components of biological ageing (senolytics, inflammasome inhibitors, mesenchymal stem cells, calorie restriction mimetics, autophagy inducers, and so on) are promising. Besides pharmacological approaches, lifestyle interventions (e.g. with regard to physical activity and diet) are known to have beneficial effects on several biological components of ageing.62,80,81 A better understanding of the biology of ageing would also probably revolutionise geriatric medicine by describing patterns of multimorbidity according to common mechanisms of multiple diseases in the same patient, paving the way to tailored interventions. Currently, geriatricians face overwhelming complexity and cascades of adverse outcomes requiring a broad knowledge of physiology and medicine and the ability to choose which symptom and/or disease (on a potentially long list) can be controlled with a positive effect on quality of life.27
Thus a significant current need is to find biological explanations for the heterogeneity of phenotypical ageing, not only from the perspective of age‐related diseases or lifespan but also from a functional perspective. This is probably one of the biggest current challenges for science and medicine, but there is reason to hope that such an approach will help us promote healthy ageing and achieve optimal longevity for as many people as possible.
Key points
There is experimental evidence of the contribution of several molecular and cellular pathways to ageing.
These hallmarks of biological ageing include genomic instability, epigenetic changes, mitochondrial dysfunction, loss of proteostasis, metabolic dysfunction, cell senescence, stem cell exhaustion, and inflammation.
Some of these pathways can be modulated by lifestyle interventions and drugs.
According to the geroscience hypothesis, accumulation of diseases and loss of functions with ageing are driven by common biological mechanisms, and measures of biological ageing may predict adverse outcomes in late life and ultimately identify interventions that extend healthspan.
Conceptual confusion is one of the obstacles to significant advances in biogerontology and geroscience: it entails difficulties in measuring the rate of ageing, defining the level of ageing, assessing when ageing starts, and so on.
The evolutionary theory of ageing is robust but should be made more precise in light of the results of the molecular biology of ageing.
References
1 1 Olshansky SJ, Carnes BA. Ever since Gompertz. Demography. 1997; 34(1):1–15.
2 2 Ruby JG, Smith M, Buffenstein R. Naked mole‐rat mortality rates defy gompertzian laws by not increasing with age. eLife. 2018; 7.
3 3 Mueller LD, Rose MR. Evolutionary theory predicts late‐life mortality plateaus. Proc Natl Acad Sci. 1996; 93(26):15249–15253.
4 4 Gavrilov LA, Gavrilova NS. Late‐life mortality is underestimated because of data errors. PLOS Biol. 2019; 17(2):e3000148.
5 5 Fries J. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980; 303(3):130–135.
6 6 Rowe JW, Kahn RL. Human aging: usual and successful. Science. 1987; 237(4811):143–149.
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