This paper discusses how growth and aging became interrelated phenomena with the creation of gerontology in the United States. I first show that the relation of growth to senescence, which had hardly attracted scientific attention before the twentieth century, started to be investigated by several experimental scientists around the 1900s. Subsequently, research on the connection between the two phenomena entered a new domain through the birth of gerontology as a scientific field comprised of various disciplines, many of which addressed (...) growth. Due to gerontologists’ efforts, the association between aging and growth became stronger and more multifaceted within the discursive and organizational matrix constituting the new science, leading to a broader definition of senescence with an ambiguous connection to chronological age. Furthermore, as gerontologists borrowed the cultural agendas as well as research methods from studies of growth, aging began to be defined as a phenomenon that could be actively controlled and managed in both social arenas and laboratory environments. (shrink)

Human life expectancy has increased dramatically through improvements in public health, housing, nutrition and general living standards. Lifespan is now limited chiefly by intrinsic senescence and its associated frailty and diseases. Understanding the biological basis of the ageing process is a major scientific challenge that will require integration of molecular, cellular, genetic and physiological approaches. This article reviews progress that has been made to date, particularly with regard to the genetic contribution to senescence and longevity, and assesses the (...) scale of the task that remains. (shrink)

The study of cellular senescence and proliferative lifespan is becoming increasingly important because of the promises of autologous cell therapy, the need for model systems for tissue disease and the implication of senescent cell phenotypes in organismal disease states such as sarcopenia, diabetes and various cancers, among others. Here, we explain the concepts of proliferative cellular lifespan and cellular senescence, and we present factors that have been shown to mediate cellular lifespan positively or negatively. We review much recent (...) literature and present potential molecular mechanisms by which lifespan mediation occurs, drawing from the fields of telomere biology, metabolism, NAD+ and sirtuin biology, growth factor signaling and oxygen and antioxidants. We conclude that cellular lifespan and senescence are complex concepts that are governed by multiple independent and interdependent pathways, and that greater understanding of these pathways, their interactions and their convergence upon specific cellular phenotypes may lead to viable therapies for tissue regeneration and treatment of age‐related pathologies, which are caused by or exacerbated by senescent cells in vivo. (shrink)

Heterochromatin, a crucial constituent of the eukaryotic nucleus with highly conserved and transcriptionally silenced characteristics, plays a pivotal role in safeguarding genome stability, regulating nuclear morphology, and mediating cell fate. Recent convincing evidence indicates that the formation and maintenance of heterochromatin are implicated in cellular senescence and age‐associated disorders. Interestingly, an attractive mechanism involving liquid–liquid phase separation (LLPS) may exert a central role in regulating heterochromatin formation and maintenance. In this review, we provide an overview of recent research to (...) illustrate the role and regulatory mechanism of the biomolecular condensates in the regulation of heterochromatin stabilization. In addition, we elucidate how heterochromatin loss contributes to cellular senescence by triggering genome instability, and explore the potential therapeutic strategies to counteract cellular senescence and age‐related pathologies by restoring heterochromatin stability. Finally, we outline current research challenges and future directions aimed at achieving a more comprehensive understanding of the link among heterochromatin regulation, phase separation, and cellular senescence, for ameliorating the effects of ageing in the future. (shrink)

Three approaches have been used to investigate the inhibitory role of the cytokinin class of phytohormones in plant senescence: external application of cytokinins, measurement of endogenous cytokinin levels before and during senescence, and manipulation of endogenous cytokinin production in transgenic plants. In transgenic plant studies, endogenous cytokinin levels are manipulated by expression of IPT, a gene encoding isopentenyl transferase. Transgenic plants expressing IPT from a variety of promoters exhibit developmental and morphological alterations and often display retarded leaf (...) class='Hi'>senescence. A recently developed autoregulatory senescence‐inhibition system targets cytokinin production quantitatively, spatially and temporally, and results in transgenic plants that exhibit significantly delayed senescence without abnormalities. These transgenic studies not only confirm the regulatory role of cytokinins in plant senescence, but also provide a way to manipulate senescence for potential agricultural applications. (shrink)

Cellular senescence is an anti‐proliferative program that restricts the propagation of cells subjected to different kinds of stress. Cellular senescence was initially described as a cell‐autonomous tumor suppressor mechanism that triggers an irreversible cell cycle arrest that prevents the proliferation of damaged cells at risk of neoplastic transformation. However, discoveries during the last decade have established that senescent cells can also impact the surrounding tissue microenvironment and the neighboring cells in a non‐cell‐autonomous manner. These non‐cell‐autonomous activities are, in (...) part, mediated by the selective secretion of extracellular matrix degrading enzymes, cytokines, chemokines and immune modulators, which collectively constitute the senescence‐associated secretory phenotype. One of the key functions of the senescence‐associated secretory phenotype is to attract immune cells, which in turn can orchestrate the elimination of senescent cells. Interestingly, the clearance of senescent cells seems to be critical to dictate the net effects of cellular senescence. As a general rule, the successful elimination of senescent cells takes place in processes that are considered beneficial, such as tumor suppression, tissue remodeling and embryonic development, while the chronic accumulation of senescent cells leads to more detrimental consequences, namely, cancer and aging. Nevertheless, exceptions to this rule may exist. Now that cellular senescence is in the spotlight for both anti‐cancer and anti‐aging therapies, understanding the precise underpinnings of senescent cell removal will be essential to exploit cellular senescence to its full potential. (shrink)

Mouse embryonic stem cells have an unlimited lifespan in cultures if they are prevented from differentiating. After differentiating, they produce cells which divide only a limited number of times. These changes seen in cultures parallel events that occur in the developing embryo, where immortal embryonic cells differentiate and produce mortal somatic ones. The data strongly suggest that differentiation initiates senescence, but this view entails additional assumptions in order to explain how the highly differentiated sexual gametes manage to remain potentially (...) immortal. Cells differentiate by blocking expression from large parts of their genome and it is suggested that losses or gains of genetic totipotency determine cellular lifespans. Cells destined to be somatic do not regain totipotency and senesce, while germ‐line cells regain complete genome expression and immortality after meiosis and gamete fusions. Losses of genetic totipotency could induce senescence by lowering the levels of repair and maintenance enzymes. (shrink)

Myotonic dystrophy type 1 (DM1) is considered a progeroid disease (i.e., causing premature aging). This hypervariable disease affects multiple systems, such as the musculoskeletal, central nervous, gastrointestinal, and others. Despite advances in understanding the underlying pathogenic mechanism of DM1, numerous gaps persist in our understanding, hindering elucidation of the heterogeneity and severity of its symptoms. Accumulating evidence indicates that the toxic intracellular RNA accumulation associated with DM1 triggers cellular senescence. These cells are in a state of irreversible cell cycle (...) arrest and secrete a cocktail of cytokines, referred to as a senescence‐associated secretory phenotype (SASP), that can have harmful effects on neighboring cells and more broadly. We hypothesize that cellular senescence contributes to the pathophysiology of DM1, and clearance of senescent cells is a promising therapeutic approach for DM1. We will discuss the therapeutic potential of different senotherapeutic drugs, especially senolytics that eliminate senescent cells, and senomorphics that reduce SASP expression. (shrink)

Skeletal muscle stem cells or satellite cells are responsible for muscle regeneration in the adult. Although satellite cells are highly resistant to stress, and display greater capacity to repair molecular damage than the committed progeny, their regenerative potential declines with age. During ageing, satellite cells switch to a state of permanent cell cycle arrest or senescence which prevents their activation. A recent study reveals that the senescence of satellite cell relies on defective autophagy, the quality control mechanism that (...) degrades damaged proteins and organelles. Molecular damage is generated by oxidative stress that also promotes epigenetic changes that activate the expression of master genes, in a double‐hit mechanism that ensures senescence. Importantly, genetic, and pharmacological correction of defective autophagy reverses satellite cell senescence and restores muscle regeneration in geriatric mice, with perspectives of modulating age‐related functional decline of muscle. This study provides new clues to understand stem cell and organismal ageing. (shrink)

Eukaryotic chromosomes end with tandem repeats of simple sequences. These GC rich repeats allow telomere replication and stabilize chromosome ends. Telomere replication involves an equilibrium of sequence loss and addition at the ends of chromosomes. Repeats are added de novo by telomerase, an unusual DNA polymerase. Telomerase is an RNP in which an essential RNA component provides the template for the added telomere repeats. Telomere length maintenance plays an essential role in cell viability.

Human diploid fibroblasts have a finite proliferative lifespan in culture, at the end of which they are ararrested with G1 phase DNA contents. Upon serum stimulation, senescent cells are deficient in carrying out a subset of early signal transduction events such as activation of protein kinase C and induction of c‐fos. Later in G1, they uniformly fail to express late G1 genes whose products are required for DNA synthesis, implying that they are unable to pass the R point. Failure to (...) pass the R point may occur because senescent cells are unable to phosphorylate the retinoblastoma protein, owing to the accumulation of inactive complexes of cyclin E/Cdk2 and possibly cyclin D/Cdk4. Senescent cells contain high amounts of p21, a potent cyclin‐dependent kinase inhibitor whose levels are also elevated in cells arrested in G1 following DNA damage, suggesting that both arrests might share a common mechanism. Cell aging is accompanied by a progressive shortening of chromosomal telomeres, which could be perceived by the cells as a form of DNA damage that gives rise to the signals that inactivate the cell cycle machinery. (shrink)

노화 현상은 생명이나 죽음과 달리 그간 철학적 관심의 대상이 되지 못 했다. 본 연구는 논화 현상에 대한 철학적 접근을 시도하기 위해서, 현대 과학의 성과에 기반하여 노화가 생명체에게 어떤 의미가 있는지를 고찰해보고자 한다. 우선 노화는 물리적 마모 현상이 아님을 지적하고, 노화를 설명하기 위해 생명체가 가진 고유한 안정성의 성격이 무엇인지를 밝히기 위해 슈뢰딩거의 생명 이론, 비평형 열역학의 소산 구조 이론 등을 검토할 것이다. 이 이론들은 생명체가 자신의 손상을 복구하는 고유한 기제를 갖고 있다는 점에 충분히 주의를 기울이지 않았다는 점에서 한계가 있다. 이 손상 (...) 복구 기제에 주목하여 노화를 설명하고자 한 싱클레어의 정보 이론은 노화가 생명체의 현재 자기와 미래 자기 사이의 연결에 관련된 문제임을 깨닫게 해 준다. 이를 통해서 우리는 노화는 현재의 자기와 미래의 자기 사이에 생적 자원을 배분하는 자연경제적 문제를 드러내며, 이 문제에 대한 근본적인 해결책은 없다는 점을 지적할 것이다. 결론적으로, 노화는 불가피하지만 그럼에도 노화의 방식에는 다양한 가능성이 있다는 것, 그리고 이러한 가능성들의 관점에서 생명체와 인간 문명을 바라보는 과제가 노화의 철학적 문제임이 드러난다. (shrink)

Two classic theories maintain that aging evolves either because of alleles whose deleterious effects are confined to late life or because of alleles with broad pleiotropic effects that increase early‐life fitness at the expense of late‐life fitness. However, empirical studies often reveal positive pleiotropy for fitness across age classes, and recent evidence suggests that selection on early‐life fitness can decelerate aging and increase lifespan, thereby casting doubt on the current consensus. Here, we briefly review these data and promote the simple (...) argument that aging can evolve under positive pleiotropy between early‐ and late‐life fitness when the deleterious effect of mutations increases with age. We argue that this hypothesis makes testable predictions and is supported by existing evidence. (shrink)

The model organism Saccharomyces cerevisiae is providing new insights into the molecular and cellular changes that are related to aging. The yeast protein Sir2p (Silent Information Regulator 2) is a histone deacetylase involved in transcriptional silencing and the control of genomic stability. Recent results have led to the identification of Sir2p as a crucial determinant of yeast life span. Dosage, intracellular localization, and activity of Sir2p all have important effects on yeast longevity. For instance, calorie restriction apparently increases yeast life (...) span by increasing Sir2p activity. Since Sir2p‐related proteins have been identified in many prokaryotic and eukaryotic organisms, the fundamental principles derived from the studies in yeast may prove valuable in directing our future research toward an understanding of the mechanisms of aging in higher eukaryotes. BioEssays 23:327–332, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Over the past four decades, philosophers have tackled a broad range of topical issues in applied ethics and political theory. These range from abortion and animal rights to multiculturalism, and the distribution of wealth and income.1 There now exists a plethora of normative theories and principles that moral and political philosophers can invoke to tackle a diverse range of practical issues. Yet, oddly, science and science policy remain relatively marginalized topics in moral and political philosophy. Few normative theories take seriously (...) the question "What constitutes just science policy?". (shrink)

Whether aging should be classified as a disease remains contentious. We propose a conceptual synthesis: aging is a meta-disease – a universal, upstream pathological condition that gives rise to the full spectrum of age-related disorders, as well as the structural and cosmetic changes historically dismissed as “normal aging.” This framework reflects a Hegelian dialectic, in which the traditional thesis (aging is a natural process) and the antithesis (aging is a disease) are integrated into a higher-order synthesis. This synthesis preserves the (...) valid insights of each while overcoming their limitations: aging is not a discrete disease, yet it is mechanistically central to disease emergence. It is thus the generative causal architecture from which age-related diseases arise—not itself a subset within pathology, but the ontological ground that gives rise to it. This reconceptualization rests on two core pillars. First, a set-theoretic nosology: aging defines the universal set A. Each age-related disease family constitutes a proper subset within A (e.g. cardiovascular disease V ⊂ A, neurodegeneration N ⊂ A). Cosmetic (K) and structural (T) changes comprise partially overlapping subsets (K ⊂ A, T ⊂ A, K ∩ T ≠ Ø). This formalism enables a precise explanation of comorbidity, multimorbidity, and the structural and cosmetic overlap of age-related conditions. Second, cellular senescence is the causal nexus: diverse molecular lesions converge on senescence, defined by irreversible proliferative arrest and activation of the senescence-associated secretory phenotype, and characterized by a distinctive multi-omic signature we term the senescome. Senescence functions as a pivotal biological switch—an “event horizon”—beyond which transient molecular insults are converted into chronic, system-wide dysfunction. Through these mechanisms, senescence is the causal generating set (S) inside A that initiates and propagates the various disease subsets. Cancer (C) is the exceptional set that reflects escape from senescence and lies largely outside S. This meta-disease framework situates geroscience within a causal ontology, defining aging as the generative source of pathology. As the antecedent ground of disease, aging thus emerges as the logical primary therapeutic target. Integrating these concepts clarifies terminology and provides formal coherence to International Classification of Diseases extension code XT9T (“Ageing-related”) and stem code MG2A (“Ageing-associated decline in intrinsic capacity”). It also provides practical levers for advancing biomarker portfolios, composite clinical trial endpoints, mechanism-based therapeutic development, regulatory frameworks, and reimbursement models for geroprotective interventions. We conclude by proposing a policy roadmap for translating the meta-disease paradigm into coordinated clinical, regulatory, and public health action, and by examining its implications for the purpose and future of medicine. (shrink)

This chapter introduces the core of the evolutionary biology of death, namely, Medawar’s mutation accumulation, and Williams’ antagonistic pleiotropy; it situates this latter theory within Williams thought, especially his critique of group selection.

Ageing is often deemed bad for people and something that ought to be eliminated. An important aspect of this normative aspect of ageing is whether ageing, i.e., senescence, is a disease. In this essay, I defend a theory of disease that concludes that ageing is not a disease, based on an account of natural function. I also criticize other arguments that lead to the same conclusion. It is important to be clear about valid reasons in this debate, since the (...) failure of bad analyses is exploited by proponents of the view that ageing is indeed a disease. Finally, I argue that there could be other reasons for attempting to eradicate senescence, which have to do with an evaluative assessment of ageing in relation to the good life. I touch on some reasons why ageing might be good for people and conclude that we cannot justify generalized statements in this regard. (shrink)

In the wake of the First World War, in an age marked by the rise of nationalist values, Italian Futurism emerged as a celebration of youthful energy, aggressiveness, and masculinity. Our postmodern century is marked by declining birth rates and the aging of the population, particularly in the Northern hemisphere. Senescence is the dominant tone of Western culture, and in this new cultural environment Futurism returns as an exaltation of technology.

Interest in the most general theory of the evolutionary ecology of life histories ever proposed—that of density-independent versus density-dependent selection—peaked in the 1980s and 1990s respectively but declined somewhat thereafter because of arguments over its theoretical coherence and some empirical failures; although as is shown here, not so much as is commonly supposed. In this article, some conceptual analyses and clarification of terms in the conditions for its application, and in the explanantia of the theory are presented. These make intelligible (...) plausible mechanisms linking the explanantia and the explananda of the theory that are both theoretically coherent and clarify what predictions it does not and does make including about senescence. (shrink)

Cell plasticity enables the dynamic changes in cell identities necessary for normal development and tissue repair. Induced cell reprogramming, which leverages this plasticity, holds great promise for regenerative medicine and personalized therapies. However, the success of cell reprogramming is often impeded by various molecular barriers, such as epigenetic marks, cell senescence, and the activation of alternative or refractory routes. In this review, we examine the cell reprogramming events that occur within or between germ layers and adult stem cell lineages (...) and propose that the overall similarity in the pre‐existing chromatin accessibility landscape is a major determinant of reprogramming efficiency from one cell type to another. A better understanding of the regulation and control of chromatin accessibility should facilitate the development of new methods and strategies to improve cell reprogramming efficiency and advance translational research. (shrink)

Understanding aging and how it affects an organism's lifespan is a fundamental problem in biology. A hallmark of aging is stem cell senescence, the decline of functionality, and number of somatic stem cells, resulting in an impaired regenerative capacity and reduced tissue function. In addition, aging is characterized by profound remodeling of the immune system and a quantitative decline of adequate immune responses, a phenomenon referred to as immune‐senescence. Yet, what is causing stem cell and immune‐senescence? This (...) review discusses experimental studies of potentially immortal Hydra which have made contributions to answering this question. Hydra transcription factor FoxO has been shown to modulate both stem cell proliferation and innate immunity, lending strong support to a role of FoxO as critical rate‐of‐aging regulator from Hydra to human. Constructing a model of how FoxO responds to diverse environmental factors provides a framework for how stem cell factors might contribute to aging. (shrink)

Ribosome biogenesis includes the making and processing of ribosomal RNAs, the biosynthesis of ribosomal proteins from their mRNAs in the cytosol and their transport to the nucleolus to assemble pre‐ribosomal particles. Several stresses including cellular senescence reduce nucleolar rRNA synthesis and maturation increasing the availability of ribosome‐free ribosomal proteins. Several ribosomal proteins can activate the p53 tumor suppressor pathway but cells without p53 can still arrest their proliferation in response to an imbalance between ribosomal proteins and mature rRNA production. (...) Recent results on senescence‐associated ribogenesis defects (SARD) show that the ribosomal protein S14 (RPS14 or uS11) can act as a CDK4/6 inhibitor linking ribosome biogenesis defects to the main engine of cell cycle progression. This work offers new insights into the regulation of the cell cycle and suggests novel avenues to design anticancer drugs. (shrink)

In this paper I provide a framework—what I refer to as ‘development theory’—for Ulanowicz’s ascendency theory of ecosystem development. Development theory is based in thermodynamics and information theory. A prominent feature of development theory is an understanding of senescence.