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.
7 7 Kaeberlein M, Rabinovitch PS, Martin GM. Healthy aging: The ultimate preventative medicine. Science. 2015; 350(6265):1191–1193.
8 8 Bergman RAM. Who is old?: Death rate in a Japanese concentration camp as a criterion of age. J Gerontol. 1948; 3(1):14–17.
9 9 Schrödinger E. What Is Life? The Physical Aspect of the Living Cell; With Mind and Matter; & Autobiographical Sketches. Cambridge University Press; 1992
10 10 Medawar P. An unsolved problem of biology. University College, London; 1952.
11 11 Williams GC. Pleiotropy, natural selection, and the evolution of senescence. Evolution. 1957; 11(4):398–411.
12 12 Hamilton WD. The moulding of senescence by natural selection. J Theor Biol. 1966; 12(1):12–45.
13 13 Charlesworth B. Evolution in Age‐Structured Populations, Cambridge University Press; 1994.
14 14 Kirkwood TB. Evolution of ageing. Nature. 1977; 270(5635):301–304.
15 15 López‐Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013; 153(6):1194–1217.
16 16 Kennedy BK, Berger SL, Brunet A, et al. Geroscience: linking aging to chronic disease. Cell 2014; 159(4):709–713.
17 17 Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med. 2019; 361(15):1475–1485.
18 18 Moskalev AA, Shaposhnikov MV, Plyusnina EN, et al. The role of DNA damage and repair in aging through the prism of Koch‐like criteria. Ageing Res Rev. 2013; 12(2):661–684.
19 19 Park CB, Larsson N‐G.
