Aging is an inherently stochastic process, and its hallmark is heterogeneity between organisms, cell types, and clonal populations, even in identical environments. The replicative lifespan of primary ...human cells is telomere dependent; however, its heterogeneity is not understood. We show that mitochondrial superoxide production increases with replicative age in human fibroblasts despite an adaptive UCP-2-dependent mitochondrial uncoupling. This mitochondrial dysfunction is accompanied by compromised Ca(2+)i homeostasis and other indicators of a retrograde response in senescent cells. Replicative senescence of human fibroblasts is delayed by mild mitochondrial uncoupling. Uncoupling reduces mitochondrial superoxide generation, slows down telomere shortening, and delays formation of telomeric gamma-H2A.X foci. This indicates mitochondrial production of reactive oxygen species (ROS) as one of the causes of replicative senescence. By sorting early senescent (SES) cells from young proliferating fibroblast cultures, we show that SES cells have higher ROS levels, dysfunctional mitochondria, shorter telomeres, and telomeric gamma-H2A.X foci. We propose that mitochondrial ROS is a major determinant of telomere-dependent senescence at the single-cell level that is responsible for cell-to-cell variation in replicative lifespan.
In 1825, the actuary Benjamin Gompertz read a paper, ‘On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies’, to the ...Royal Society in which he showed that over much of the adult human lifespan, age-specific mortality rates increased in an exponential manner. Gompertz's work played an important role in shaping the emerging statistical science that underpins the pricing of life insurance and annuities. Latterly, as the subject of ageing itself became the focus of scientific study, the Gompertz model provided a powerful stimulus to examine the patterns of death across the life course not only in humans but also in a wide range of other organisms. The idea that the Gompertz model might constitute a fundamental ‘law of mortality’ has given way to the recognition that other patterns exist, not only across the species range but also in advanced old age. Nevertheless, Gompertz's way of representing the function expressive of the pattern of much of adult mortality retains considerable relevance for studying the factors that influence the intrinsic biology of ageing. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.
On the evolution of cellular senescence Kowald, Axel; Passos, João F.; Kirkwood, Thomas B. L.
Aging Cell,
December 2020, Letnik:
19, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The idea that senescent cells are causally involved in aging has gained strong support from findings that the removal of such cells alleviates many age‐related diseases and extends the life span of ...mice. While efforts proceed to make therapeutic use of such discoveries, it is important to ask what evolutionary forces might have been behind the emergence of cellular senescence, in order better to understand the biology that we might seek to alter. Cellular senescence is often regarded as an anti‐cancer mechanism, since it limits the division potential of cells. However, many studies have shown that senescent cells often also have carcinogenic properties. This is difficult to reconcile with the simple idea of an anti‐cancer mechanism. Furthermore, other studies have shown that cellular senescence is involved in wound healing and tissue repair. Here, we bring these findings and ideas together and discuss the possibility that these functions might be the main reason for the evolution of cellular senescence. Furthermore, we discuss the idea that senescent cells might accumulate with age because the immune system had to strike a balance between false negatives (overlooking some senescent cells) and false positives (destroying healthy body cells).
Cellular senescence is often regarded as an anti‐cancer mechanism although many studies have shown that senescent cells often also have carcinogenic properties. Here, we discuss the possibility that actually wound healing, tissue repair, and development might be the main reason for the evolution of cellular senescence. We also suggest that senescent cells might accumulate with age because the immune system has to strike a balance between false negatives and false positives.
Understanding why and how senescence evolved is of great importance in investigating the multiple, complex mechanisms that influence the course of ageing in humans and other organisms. Compelling ...arguments eliminate the idea that death is generally programmed by genes for ageing, but there is still a widespread tendency to interpret data in terms of loosely defined ‘age regulation’, which does not usually make either evolutionary or mechanistic sense. This review critically addresses the role of natural selection in shaping ageing within the life history and examines the implications for research on genetic pathways that influence the life span. It is recognised that in exceptional circumstances the possibility exists for selection to favour limiting survival. In acknowledging that, at least in theory, ageing might occasionally be adaptive, however, the high barriers to validating actual instances of adaptive ageing are made clear.
Weak grip strength (GS) is a key component of sarcopenia and frailty and a powerful predictor of mortality, morbidity and disability. Despite increasing interest in understanding GS across the ...lifespan, little is known about GS decline in the very old (aged ≥85). We examined trajectories of GS in very old adults and identified the determinants.
GS (kg) was measured four times over 5 years in 319 men and 526 women participating in the Newcastle 85+ Study. A weak GS sub-cohort was identified as having strength of ≤27 kg (men), and ≤16 kg (women) at baseline and follow-up. Mixed models were used to establish trajectories of GS and associated factors in all participants, men and women, and in those with weak GS.
Men's mean grip strength was 24.42 (SD = 6.77) kg, and women's 13.23 (4.42) kg (p<0.001) at baseline, with mean absolute change of -5.27 (4.90) kg and -3.14 (3.41), respectively (p<0.001) by 5-year follow-up. In the time-only mixed model, men experienced linear annual decline in GS of -1.13 (0.8) kg (β (SE), p<0.001), whilst women's decline although slower, accelerated by -0.06 (0.02) kg (p = 0.01) over time. In the saturated model, higher baseline physical activity, height, fat-free mass, better self-rated health, and not having arthritis in hand(s) were associated with stronger GS initially in both sexes. Annual GS decline in men and participants with weak GS who were highly physically active was slower by 0.95 and 0.52 kg, respectively compared with inactive counterparts.
Grip strength decline in the very old followed linear (men) and curvilinear (women) trends. High levels of physical activity were protective of GS loss in men (but not in women) and in those with weak GS. Thus maintaining muscle strength in later life is important to reduce the morbidity and mortality in the very old.
Cellular senescence, a state of irreversible cell cycle arrest, is thought to help protect an organism from cancer, yet also contributes to ageing. The changes which occur in senescence are ...controlled by networks of multiple signalling and feedback pathways at the cellular level, and the interplay between these is difficult to predict and understand. To unravel the intrinsic challenges of understanding such a highly networked system, we have taken a systems biology approach to cellular senescence. We report a detailed analysis of senescence signalling via DNA damage, insulin-TOR, FoxO3a transcription factors, oxidative stress response, mitochondrial regulation and mitophagy. We show in silico and in vitro that inhibition of reactive oxygen species can prevent loss of mitochondrial membrane potential, whilst inhibition of mTOR shows a partial rescue of mitochondrial mass changes during establishment of senescence. Dual inhibition of ROS and mTOR in vitro confirmed computational model predictions that it was possible to further reduce senescence-induced mitochondrial dysfunction and DNA double-strand breaks. However, these interventions were unable to abrogate the senescence-induced mitochondrial dysfunction completely, and we identified decreased mitochondrial fission as the potential driving force for increased mitochondrial mass via prevention of mitophagy. Dynamic sensitivity analysis of the model showed the network stabilised at a new late state of cellular senescence. This was characterised by poor network sensitivity, high signalling noise, low cellular energy, high inflammation and permanent cell cycle arrest suggesting an unsatisfactory outcome for treatments aiming to delay or reverse cellular senescence at late time points. Combinatorial targeted interventions are therefore possible for intervening in the cellular pathway to senescence, but in the cases identified here, are only capable of delaying senescence onset.
The relationship between age-related frailty and the underlying processes that drive changes in health is currently unclear. Considered individually, most blood biomarkers show only weak ...relationships with frailty and ageing. Here, we examined whether a biomarker-based frailty index (FI-B) allowed examination of their collective effect in predicting mortality compared with individual biomarkers, a clinical deficits frailty index (FI-CD), and the Fried frailty phenotype.
We analyzed baseline data and up to 7-year mortality in the Newcastle 85+ Study (n = 845; mean age 85.5). The FI-B combined 40 biomarkers of cellular ageing, inflammation, haematology, and immunosenescence. The Kaplan-Meier estimator was used to stratify participants into FI-B risk strata. Stability of the risk estimates for the FI-B was assessed using iterative, random subsampling of the 40 FI-B items. Predictive validity was tested using Cox proportional hazards analysis and discriminative ability by the area under receiver operating characteristic (ROC) curves.
The mean FI-B was 0.35 (SD, 0.08), higher than the mean FI-CD (0.22; SD, 0.12); no participant had an FI-B score <0.12. Higher values of each FI were associated with higher mortality risk. In a sex-adjusted model, each one percent increase in the FI-B increased the hazard ratio by 5.4 % (HR, 1.05; CI, 1.04-1.06). The FI-B was more powerful for mortality prediction than any individual biomarker and was robust to biomarker substitution. The ROC analysis showed moderate discriminative ability for 7-year mortality (AUC for FI-CD = 0.71 and AUC for FI-B = 0.66). No individual biomarker's AUC exceeded 0.61. The AUC for combined FI-CD/FI-B was 0.75.
Many biological processes are implicated in ageing. The systemic effects of these processes can be elucidated using the frailty index approach, which showed here that subclinical deficits increased the risk of death. In the future, blood biomarkers may indicate the nature of the underlying causal deficits leading to age-related frailty, thereby helping to expose targets for early preventative interventions.
Summary
The evolution of the aging process has long been a biological riddle, because it is difficult to explain the evolution of a trait that has apparently no benefit to the individual. Over ...60 years ago, Medawar realized that the force of natural selection declines with chronological age because of unavoidable environmental risks. This forms the basis of the mainstream view that aging arises as a consequence of a declining selection pressure to maintain the physiological functioning of living beings forever. Over recent years, however, a number of articles have appeared that nevertheless propose the existence of specific aging genes; that is, that the aging process is genetically programmed. If this view were correct, it would have serious implications for experiments to understand and postpone aging. Therefore, we studied in detail various specific proposals why aging should be programmed. We find that not a single one withstands close scrutiny of its assumptions or simulation results. Nonprogrammed aging theories based on the insight of Medawar (as further developed by Hamilton and Charlesworth) are still the best explanation for the evolution of the aging process. We hope that this analysis helps to clarify the problems associated with the idea of programmed aging.
Grip strength is a simple but powerful predictor of future disability, morbidity, and mortality. The relation between grip strength and future mortality has been shown, not only in older people but ...also in middle-aged 2 and young people.
Genetic and pharmacological intervention studies have identified evolutionarily conserved and functionally interconnected networks of cellular energy homeostasis, nutrient-sensing, and genome damage ...response signaling pathways, as prominent regulators of longevity and health span in various species. Mitochondria are the primary sites of ATP production and are key players in several other important cellular processes. Mitochondrial dysfunction diminishes tissue and organ functional performance and is a commonly considered feature of the aging process. Here we review the evidence that through reciprocal and multilevel functional interactions, mitochondria are implicated in the lifespan modulation function of these pathways, which altogether constitute a highly dynamic and complex system that controls the aging process. An important characteristic of these pathways is their extensive crosstalk and apparent malleability to modification by non-invasive pharmacological, dietary, and lifestyle interventions, with promising effects on lifespan and health span in animal models and potentially also in humans.
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