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Pathy's Principles and Practice of Geriatric Medicine. Группа авторов
Читать онлайн.Название Pathy's Principles and Practice of Geriatric Medicine
Год выпуска 0
isbn 9781119484295
Автор произведения Группа авторов
Жанр Медицина
Издательство John Wiley & Sons Limited
Mitochondrial dysfunction
According to the historical mitochondrial free radical ‘theory’ of ageing,34 progressive mitochondrial dysfunction reduces energy availability and increases the production of reactive oxygen species (ROS) that damage macromolecules, contributing to ageing. Nevertheless, this theory has been reshaped in light of observations that (i) increased ROS may prolong lifespan in model organisms, (ii) increased ROS production and oxidative damage do not accelerate ageing in mice, and (iii) experimental mitochondrial dysfunction may accelerate ageing without ROS production.35 Therefore, ROS may be considered a stress‐induced survival signal response to ageing‐related damage, which will eventually aggravate the process if antioxidant systems are overwhelmed. ROS‐independent mechanisms of mitochondrial dysfunction include a propensity to stress‐induced permeabilisation, reduced mitochondria biogenesis, and reduced quality control by autophagy (see the following section).15
Interestingly, mitochondrial metabolic function can now be measured in vivo, and it has been shown to be associated with muscle strength and mobility in older people.36 Measures of mitochondrial physiology and function may thus be powerful markers of biological ageing but need careful standardisation.27
Loss of proteostasis
Several quality control mechanisms maintain intracellular protein homeostasis, or proteostasis: misfolded proteins can be refolded by chaperone proteins or degraded by the ubiquitin‐proteasome system and lysosomal pathways (the latter phenomenon being referring as autophagy). An increase in protein misfolding (due to cellular stress, for instance) and/or failure of quality control mechanisms is thought to contribute to ageing and age‐related diseases, typically Alzheimer’s and cataracts.37,38 Mice deficient in the CHIP co‐chaperone exhibit accelerated‐ageing phenotypes and reduced lifespan,39 and mice overexpressing Atg5 (a protein essential for autophagosome formation) have better motor function and increased lifespan. In humans, autophagy appears to be better maintained in offspring of individuals with exceptional longevity and is associated with higher effector functions of T lymphocytes. Interestingly, the lifespan‐extending effect of drugs (e.g. rapamycin) shown in mice may be mediated by their autophagy‐inducing properties.40 Thus, loss of mechanisms controlling protein homeostasis, especially autophagy, may be involved in ageing, and there is growing interest in measuring these mechanisms as markers of biological age.27
Metabolic dysfunction
Major metabolic changes during ageing are insulin resistance, body composition modifications (increase in visceral fat mass and decrease in skeletal muscle mass), and decline in both sex steroids and hormones of the somatotrophic axis. This axis comprises the growth hormone and insulin‐like growth factor (IGF‐1), which shares a downstream intracellular pathway with insulin, thereby signalling nutrient abundance and anabolism. Interestingly, genetically driven reductions in the functions of GH, IGF‐1 receptors, insulin receptors, and their intracellular effectors (including mammalian target of rapamycin, mTOR) are associated with longevity in humans and model organisms.41,42 More comprehensively, insulin/IGF‐1 axis activity decreases during ageing, whereas its constitutive impairment extends longevity. This paradox may be understood if we consider intense trophic and anabolic activity as an accelerator of ageing, and the downregulation of insulin/IGF‐1 and mTOR pathways as defensive responses against systemic damage during ageing, aimed at reducing cell growth and metabolism.15,43
Furthermore, both dietary restriction and drugs that mimic it (e.g. rapamycin) were shown to increase lifespan in animal models (including mice) through the effect on the insulin/IGF‐1 pathway, emphasising the role of deregulated nutrient‐sensing in the biology of ageing.44,45 Of note, mTOR inhibitors are currently approved and used as immunosuppressive drugs for recipients of organ transplants. Nevertheless, given their side effects, their net effect on human ageing remains to be determined. Metformin is also seen as a potential anti‐ageing drug due to its positive effect on deregulated nutrient sensing and mitochondrial dysfunction, DNA damage, and inflammation.46
Cell senescence
Cellular senescence is a state of stable arrest of the cell cycle coupled to phenotypic changes, including the production of several molecules (especially matrix metalloproteases and pro‐inflammatory cytokines) collectively known as the senescence‐associated secretory phenotype (SASP),47 that contributes to senescence spreading among others cells, inflammation, and tissue dysfunction. Of note, a better understanding of molecular mechanisms of cell senescence led to a more complex picture of a multi‐step progressive and dynamic phenomenon rather than a static endpoint.48
As cited earlier, cellular senescence was originally described by Hayflick in human fibroblasts in vitro 21; this phenomenon, called replicative senescence, is now known to be caused by telomere shortening. Nevertheless, cell senescence can be triggered by other stimuli during ageing, notably non‐telomeric DNA damage and excessive mitogenic signalling, particularly by the p16Ink4a tumour‐suppressor protein upon epigenetic de‐repression of the ink4/ark locus.49 p16Ink4a positively correlates with age in various tissues in mice and human skin.50,51 In a meta‐analysis of 372 genome‐wide association studies (GWASs) aiming at identifying susceptibility polymorphisms for age‐associated diseases, the ink4/ark locus was linked to the greatest number of diseases, including Alzheimer’s, cardiovascular diseases, cancer, and type 2 diabetes.52 Furthermore, the number of cells expressing p16Ink4a in muscular fat correlates with muscle strength and walking performance.53
Since the number of senescent cells is positively associated with age, it has been postulated that cell senescence contributes to ageing. However, this phenomenon may also be seen as a mechanism to prevent the propagation of damaged and potentially oncogenic cells and to trigger their elimination by the immune system. Tissue dysfunction and ageing could then only be explained by an impaired turnover of cells due to reduced clearance of senescent cells and/or reduced regeneration by progenitor cells. As described previously for free radicals, this dual role of cell senescence in ageing can reconcile apparently contradictory effects of experimental modulation of p16Ink4a activity on health and lifespan in mice.15,54‐56
Interestingly, the selective elimination of senescent cells attenuates age‐related deterioration of several organs and extends lifespan in mice,57 and the potential anti‐ageing effects of senolytic drugs is an intense area of research.58
Stem cell exhaustion
Stem cells are present in all tissues and organs after development and regenerate damaged tissues throughout life. The repair and regenerative potential of many tissues declines with ageing due to functional attrition in several stem cell compartments (e.g. hematopoietic, neural, mesenchymal, and intestinal epithelial stem cells, as well as satellite cells in muscles).59 Stem cell exhaustion is seen as an integrative consequence of several components of biological ageing discussed in this chapter, including DNA damage, epigenetic alterations, telomere shortening, cellular senescence, and mitochondrial dysfunction.15 Hematopoietic stem cells are probably the most‐studied (partly because they are more easily available), and stem cell exhaustion is thought to be a major driver of immunosenescence (see the next section).
As mentioned earlier, reduced regeneration of tissues by progenitor cells may theoretically contribute to tissue dysfunction and, thus, to the ageing process. However, stem cell exhaustion is difficult to measure before the onset of its clinical consequences, and evidence is scarce for a contribution of this phenomenon to ageing. It is worth mentioning that transplantation of muscle‐derived stem cells from young mice extends the health‐ and lifespan of progeroid mice, even in tissues with undetectable