Edmund Vincent Cowdry and the Making of Gerontology as a Multidisciplinary Scientific Field in the United States

The Canadian–American biologist Edmund Vincent Cowdry played an important role in the birth and development of the science of aging, gerontology. In particular, he contributed to the growth of gerontology as a multidisciplinary scientific field in the United States during the 1930s and 1940s. With the support of the Josiah Macy, Jr. Foundation, he organized the first scientific conference on aging at Woods Hole, Massachusetts, where scientists from various fields gathered to discuss aging as a scientific research topic. He also edited Problems of Ageing (1939), the first handbook on the current state of aging research, to which specialists from diverse disciplines contributed. The authors of this book eventually formed the Gerontological Society in 1945 as a multidisciplinary scientific organization, and some of its members, under Cowdry’s leadership, formed the International Association of Gerontology in 1950. This article historically traces this development by focusing on Cowdry’s ideas and activities. I argue that the social and economic turmoil during the Great Depression along with Cowdry’s training and experience as a biologist – cytologist in particular – and as a textbook editor became an important basis of his efforts to construct gerontology in this direction.     

Topical Problems in Gerontology

Biophysics - Abstract—Currently, gerontology is changing its priorities. If yesterday the main was search for biological mechanisms of aging (independent work of gerontologists), that today...     

Robust,universal biomarker assay to detect senescent cells in biological specimens

Cellular senescence contributes to organismal development, aging, and diverse pathologies, yet available assays to detect senescent cells remain unsatisfactory. Here, we designed and synthesized a lipophilic, biotin‐linked Sudan Black B (SBB) analogue suitable for sensitive and specific, antibody‐enhanced detection of lipofuscin‐containing senescent cells in any biological material. This new hybrid histo‐/immunochemical method is easy to perform, reliable, and universally applicable to assess senescence in biomedicine, from cancer research to gerontology.     

Social context, stress, and plasticity of aging

Positive social contact is an important factor in healthy aging, but our understanding of how social interactions influence senescence is incomplete. As life expectancy continues to increase because of reduced death rates among elderly, the beneficial role of social relationships is emerging as a cross-cutting theme in research on aging and healthspan. There is a need to improve knowledge on how behavior shapes, and is shaped by, the social environment, as well as needs to identify and study biological mechanisms that can translate differences in the social aspects of behavioral efforts, relationships, and stress reactivity (the general physiological and behavioral response-pattern to harmful, dangerous or unpleasant situations) into variation in aging. Honey bees (Apis mellifera) provide a genetic model in sociobiology, behavioral neuroscience, and gerontology that is uniquely sensitive to social exchange. Different behavioral contact between these social insects can shorten or extend lifespan more than 10-fold, and some aspects of their senescence are reversed by social cues that trigger aged individuals to express youthful repertoires of behavior. Here, I summarize how variation in social interactions contributes to this plasticity of aging and explain how beneficial and detrimental roles of social relationships can be traced from environmental and biological effects on honey bee physiology and behavior, to the expression of recovery-related plasticity, stress reactivity, and survival during old age. This system provides intriguing opportunities for research on aging.     

DNA 与衰老

衰老是生物体各种功能的普遍衰弱,以及抵抗环境伤害和恢复生理稳态的降低过程。衰老、衰老的原因、衰老的机理及衰老与疾病、衰老与死亡的关系,一直是生物及医学领域的科学家们积极探讨的问题。衰老这一极其复杂的生物学过程,涉及物理、化学、生物、医学诸领域。现已发展的近300种衰老学说分别从整体、器官、细胞、分子水平对生物衰老的机制进行了阐述。本文将从分子的角度阐述生物信息分子－DNA及其相关物质与生物衰老的关系。     

Insulin‐like growth factor‐1 regulates the SIRT1‐p53 pathway in cellular senescence

Cellular senescence, which is known to halt proliferation of aged and stressed cells, plays a key role against cancer development and is also closely associated with organismal aging. While increased insulin‐like growth factor (IGF) signaling induces cell proliferation, survival and cancer progression, disrupted IGF signaling is known to enhance longevity concomitantly with delay in aging processes. The molecular mechanisms involved in the regulation of aging by IGF signaling and whether IGF regulates cellular senescence are still poorly understood. In this study, we demonstrate that IGF‐1 exerts a dual function in promoting cell proliferation as well as cellular senescence. While acute IGF‐1 exposure promotes cell proliferation and is opposed by p53, prolonged IGF‐1 treatment induces premature cellular senescence in a p53‐dependent manner. We show that prolonged IGF‐1 treatment inhibits SIRT1 deacetylase activity, resulting in increased p53 acetylation as well as p53 stabilization and activation, thus leading to premature cellular senescence. In addition, either expression of SIRT1 or inhibition of p53 prevented IGF‐1‐induced premature cellular senescence. Together, these findings suggest that p53 acts as a molecular switch in monitoring IGF‐1‐induced proliferation and premature senescence, and suggest a possible molecular connection involving IGF‐1‐SIRT1‐p53 signaling in cellular senescence and aging.     

Hypertrophy hypothesis as an alternative explanation of the phenomenon of replicative aging of yeast

This paper summarizes numerous arguments demonstrating that the hypothesis of accumulation of the senescence factor, which was the basis for introducing yeast to the group of model organisms of gerontology, finds no experimental support. Among several candidates for the role of the causative agents of replicative aging, only one - hypertrophy - always accompanies symptoms of aging, not only in Saccharomyces cerevisiae, but also in Schizosaccharomyces pombe.     

Activation of epidermal growth factor receptor signaling mediates cellular senescence induced by certain pro‐inflammatory cytokines

It is well established that inflammation in the body promotes organism aging, and recent studies have attributed a similar effect to senescent cells. Considering that certain pro‐inflammatory cytokines can induce cellular senescence, systematically evaluating the effects of pro‐inflammatory cytokines in cellular senescence is an important and urgent scientific problem, especially given the ongoing surge in aging human populations. Treating IMR90 cells and HUVECs with pro‐inflammatory cytokines identified six factors able to efficiently induce cellular senescence. Of these senescence‐inducing cytokines, the activity of five (namely IL‐1β, IL‐13, MCP‐2, MIP‐3α, and SDF‐1α) was significantly inhibited by treatment with cetuximab (an antibody targeting epidermal growth factor receptor [EGFR]), gefitinib (a small molecule inhibitor of EGFR), and EGFR knockdown. In addition, treatment with one of the senescence‐inducing cytokines, SDF‐1α, significantly increased the phosphorylation levels of EGFR, as well as Erk1/2. These results suggested that pro‐inflammatory cytokines induce cellular senescence by activating EGFR signaling. Next, we found that EGF treatment could also induce cellular senescence of IMR90 cells and HUVECs. Mechanically, EGF induced cellular senescence via excessive activation of Ras and the Ras‐BRaf‐Erk1/2 signaling axis. Moreover, EGFR activation induced IMR90 cells to secrete certain senescence‐associated secretory phenotype factors (IL‐8 and MMP‐3). In summary, we report that certain pro‐inflammatory cytokines induce cellular senescence through activation of the EGFR‐Ras signaling pathway. Our study thus offers new insight into a long‐ignored mechanism by which EGFR could regulate cellular senescence and suggests that growth signals themselves may catalyze aging under certain conditions.     

细胞衰老与肿瘤治疗

人口老龄化是全世界都面临的重大挑战,随着老年人口的增加,肿瘤等衰老相关疾病发病率随之升高.流行病学调查结果显示,大约2/3的新增肿瘤患者为65岁以上的老年人,并且这一比例在不断攀升.细胞衰老是指在DNA损伤或癌基因失调等一系列条件下引起的稳定的细胞周期阻滞,并伴有形态、生化及表观遗传的改变.大量研究证明细胞衰老对抑制潜在癌细胞增殖具有重要作用.然而,目前研究认为除了抑制肿瘤发生,细胞衰老也可能促进肿瘤的演进,细胞衰老对肿瘤发挥了双刃剑作用.因此,深入了解细胞衰老与肿瘤之间的联系,充分利用细胞衰老对肿瘤抑制功能,规避其对肿瘤的促进作用可为肿瘤的治疗提供更多可能的选择.     

Cellular aging beyond cellular senescence: Markers of senescence prior to cell cycle arrest in vitro and in vivo

The field of research on cellular senescence experienced a rapid expansion from being primarily focused on in vitro aspects of aging to the vast territories of animal and clinical research. Cellular senescence is defined by a set of markers, many of which are present and accumulate in a gradual manner prior to senescence induction or are found outside of the context of cellular senescence. These markers are now used to measure the impact of cellular senescence on aging and disease as well as outcomes of anti‐senescence interventions, many of which are at the stage of clinical trials. It is thus of primary importance to discuss their specificity as well as their role in the establishment of senescence. Here, the presence and role of senescence markers are described in cells prior to cell cycle arrest, especially in the context of replicative aging and in vivo conditions. Specifically, this review article seeks to describe the process of “cellular aging”: the progression of internal changes occurring in primary cells leading to the induction of cellular senescence and culminating in cell death. Phenotypic changes associated with aging prior to senescence induction will be characterized, as well as their effect on the induction of cell senescence and the final fate of cells reviewed. Using published datasets on assessments of senescence markers in vivo, it will be described how disparities between quantifications can be explained by the concept of cellular aging. Finally, throughout the article the applicational value of broadening cellular senescence paradigm will be discussed.     

The variability of the mitochondrial genome in human aging: a key for life and death?

The impressive performance of the research in mitochondrial genetics and human aging in the last decade outlines a new scenery in which the inherited variation of the mitochondrial genome (mtDNA) may play a role in rate and quality of aging. This variation in humans was initially looked at as nearly neutral, and useful just for the reconstruction of human population history. However, recent data suggest that different mtDNA molecules are qualitatively different from each other. The aim of this paper is to discuss current ideas on the relationships among mitochondrial function, mtDNA inherited variation, and aging. The main processes where the mitochondrion is involved and the importance these processes have on aging and death of individuals will be described. A possible connection between programmed death phenomena (mitoptosis, apoptosis, phenoptosis) and rate and quality of aging will be discussed. Finally, the possible role played in these processes by the mtDNA germline variation will be explored.     

Biological anthropology of aging--past,present and future

Biological anthropologists have a strong tradition of studying growth and development and research on aging has been limited. This paper explores the past and current contribution of biological anthropologists to the field of aging through an examination of the American Journal of Physical Anthropology (AJPA) and the American Journal of Human Biology (AJHB). It is clear from this survey that biological anthropologists and human biologists have predominantly studied growth and developmental processes relative to aging. However, there is a trend of increasing interest in aging over time. In the AJHB, papers discussing chronic disease were predominant, followed by reproductive aging (19%), bone aging (15%) and body composition (10%). Within the AJPA, the majority of articles were in the field of human biology (43%) and bioarchaelogy (42%) with a lesser contribution from primatology (14%) and dermatogliphics (1%). Biological anthropologists still have great potential to make contributions to gerontology with our evolutionary and holistic perspectives and focus on cross-cultural research.     

Negative growth effectors and cellular senescence.

Current studies suggest a genetic program governs the lifespan of each organism. Using cellular senescence as a model system, components of this program for aging have been sought. Human diploid fibroblasts, upon reaching senescence, express active inhibitors of DNA synthesis. It is believed that such inhibitors could be members of a new family of negative growth effectors involved in the pathway to senescence. Factors capable of inhibiting DNA synthesis in a similar manner have also been identified from human quiescent fibroblasts and liver cells as well as from quiescent rodent liver cells. The relationship of these inhibitors to previously identified negative growth effectors and aging are discussed.     

Insights from comparative analyses of aging in birds and mammals

Many laboratory models used in aging research are inappropriate for understanding senescence in mammals, including humans, because of fundamental differences in life history, maintenance in artificial environments, and selection for early aging and high reproductive rate. Comparative studies of senescence in birds and mammals reveal a broad range in rates of aging among a variety of taxa with similar physiology and patterns of development. These comparisons suggest that senescence is a shared property of all vertebrates with determinate growth, that the rate of senescence has been modified by evolution in response to the potential life span allowed by extrinsic mortality factors, and that most variation among species in the rate of senescence is independent of commonly ascribed causes of aging, such as oxidative damage. Individuals of potentially long‐lived species, particularly birds, appear to maintain high condition to near the end of life. Because most individuals in natural populations of such species die of aging‐related causes, these populations likely harbor little genetic variation for mechanisms that could extend life further, or these mechanisms are very costly. This, and the apparent evolutionary conservatism in the rate of increase in mortality with age, suggests that variation in the rate of senescence reflects fundamental changes in organism structure, likely associated with the rate of development, rather than physiological or biochemical processes influenced by a few genes. Understanding these evolved differences between long‐lived and short‐lived organisms would seem to be an essential foundation for designing therapeutic interventions with respect to human aging and longevity.     

Telomeres and telomerase in the fetal origins of cardiovascular disease: a review

Telomeres are noncoding functional DNA repeat sequences at the ends of chromosomes that decrease in length by a predictable amount at each cell division. When the telomeres become critically short, the cell is no longer able to replicate and enters cellular senescence. Recent work has shown that within individuals, telomere length tracks with cardiovascular health and aging and is also affected by growth variation, both prenatally and postnatally. Therefore telomere length can be a marker of both growth history (cell division) and tissue function (senescence). Relationships between early growth and later health have emerged as a research focus in the epidemiology of chronic diseases of aging, such as heart disease and diabetes. The "fetal origins" literature has demonstrated that hormonal and nutritional aspects of the intrauterine environment not only affect fetal growth but also can permanently alter the metabolic program of the individual. Smaller infants tend to have a higher risk of developing cardiovascular disease. Much less attention has been paid to possible genetic links between the processes of early growth and later disease. Our aim in this review is to summarize evidence for one such genetic mechanism, telomere attrition, that may underlie the fetal origins of cardiovascular disease and to discuss this mechanism in light of the evolution of senescence.     

Molecular and chemical genetic approaches to developmental origins of aging and disease in zebrafish

The incidence of diseases increases rapidly with age, accompanied by progressive deteriorations of physiological functions in organisms. Aging-associated diseases are sporadic but mostly inevitable complications arising from senescence. Senescence is often considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena over the dynamic process of aging. The association between early development and late-onset disease with advancing age is thought to come from a consequence of developmental plasticity, the phenomenon by which one genotype can give rise to a range of physiologically and/or morphologically adaptive states in response to different environmental or genetic perturbations. On the one hand, we hypothesized that the future aging process can be predictive based on adaptivity during the early developmental period. Modulating the thresholds of adaptive plasticity by chemical genetic approaches, we have been investigating whether any relationship exists between the regulatory mechanisms that function in early development and in senescence using the zebrafish (Danio rerio), a small freshwater fish and a useful model animal for genetic studies. We have successfully conducted experiments to isolate zebrafish mutants expressing apparently altered senescence phenotypes during embryogenesis (“embryonic senescence”), subsequently showing shortened lifespan in adulthoods. We anticipate that previously uncharacterized developmental genes may mediate the aging process and play a pivotal role in senescence. On the other hand, unexpected senescence-related genes might also be involved in the early developmental process and regulation. The ease of manipulation using the zebrafish system allows us to conduct an exhaustive exploration of novel genes and small molecular compounds that can be linked to the senescence phenotype, and thereby facilitates searching for the evolutionary and developmental origins of aging in vertebrates. This article is part of a Special Issue entitled: Animal Models of Disease.     

清除衰老细胞在衰老与老龄化相关疾病中的研究进展

衰老是一个新兴的重要研究领域,随着该领域相关知识的积累和技术的进步,人们逐渐意识到衰老本身可以被针对性地干预,实现延长寿命并且延缓衰老相关疾病的发生发展,具有重要的科学和现实意义.引起个体衰老的众多因素中,衰老细胞的积累被认为是导致器官衰老发生退行性变,最终引起衰老相关疾病的重要原因.近年来,多项研究表明,清除体内衰老细胞可以延缓多种衰老相关疾病的发生,直接证明了衰老细胞是导致衰老相关疾病的重要原因之一,为治疗衰老相关疾病提供了新靶点.细胞衰老是由于损伤积累诱发了细胞周期抑制通路的激活,细胞永久地退出细胞增殖周期.衰老细胞会发生细胞形态、转录谱、蛋白质稳态、表观遗传以及代谢等系列特征的改变,同时衰老细胞对凋亡发生抵抗从而在体内多器官组织积累.衰老细胞会激活炎症因子分泌通路,导致组织局部非感染性炎症微环境,进而导致器官退行性变及多种衰老相关疾病的发生发展.因此针对衰老细胞对凋亡抵抗的特性,多个研究小组通过筛选小分子化合物库,发现某些化合物能够选择性清除衰老细胞,这些小分子化合物被称为"senolytics",意为"衰老细胞杀伤性化合物".衰老细胞杀伤性化合物在多种衰老相关疾病动物模型中能够延缓疾病的发展并延长哺乳动物寿命.因此,靶向杀伤衰老细胞对多种衰老相关疾病的治疗从而提高健康寿命具有重要的临床应用前景.除靶向杀伤衰老细胞策略以外,干细胞移植、基因编辑、异体共生等策略在抗衰老研究发展中也具有重要意义,具有启发性.本文通过汇总近期衰老细胞清除领域的重要进展和多种抗衰老策略,将细胞衰老研究发展史做简要梳理,就细胞衰老与衰老相关疾病的关系作一综述,重点讨论衰老细胞在多种衰老相关疾病中作为治疗靶点的应用潜力,并就其局限性和进一步的研究方向进行探讨.     

The search for evolutionary developmental origins of aging in zebrafish: a novel intersection of developmental and senescence biology in the zebrafish model system

Senescence may be considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena during the process of aging. We investigated whether any relationship exists between the regulatory mechanisms that function in early development and in senescence using the zebrafish (Danio rerio), a small freshwater fish and a useful model animal for genetic studies. We conducted experiments to isolate zebrafish mutants expressing an apparent senescence phenotype during embryogenesis (embryonic senescence). Some of the genes we thereby identified had already been associated with cellular senescence and chronological aging in other organisms, but many had not yet been linked to these processes. Complete loss-of-function of developmentally essential genes induce embryonic (or larval) lethality, whereas it seems like their partial loss-of-function (i.e., decrease-of-function by heterozygote or hypomorphic mutations) still remains sufficient to go through the early developmental process because of its adaptive plasticity or rather heterozygote advantage. However, in some cases, such partial loss-of-function of genes compromise normal homeostasis due to haploinsufficiency later in adult life having many environmental stress challenges. By contrast, any heterozygote-advantageous genes might gain a certain benefit(s) (much more fitness) by such partial loss-of-function later in life. Physiological senescence may evolutionarily arise from both genetic and epigenetic drifts as well as from losing adaptive developmental plasticity in face of stress signals from the external environment that interacts with functions of multiple genes rather than effects of only a single gene mutation or defect. Previously uncharacterized developmental genes may thus mediate the aging process and play a pivotal role in senescence. Moreover, unexpected senescence-related genes might also be involved in the early developmental process and regulation. We wish to ascertain whether we can identify such genes promptly in a comprehensive manner. The ease of manipulation using the zebrafish system allows us to conduct an exhaustive exploration of novel genes and small molecular compounds that can be linked to the senescence phenotype and thereby facilitates searching for the evolutionary and developmental origins of aging in vertebrates.     

Upregulation of the gene encoding a cytoplasmic dynein intermediate chain in senescent human cells

Normal human somatic cells, unlike cancer cells, stop dividing after a limited number of cell divisions through the process termed cellular senescence or replicative senescence, which functions as a tumor-suppressive mechanism and may be related to organismal aging. By means of the cDNA subtractive hybridization, we identified eight genes upregulated during normal chromosome 3-induced cellular senescence in a human renal cell carcinoma cell line. Among them is the DNCI1 gene encoding an intermediate chain 1 of the cytoplasmic dynein, a microtubule motor that plays a role in chromosome movement and organelle transport. The DNCI1 mRNA was also upregulated during in vitro aging of primary human fibroblasts. In contrast, other components of cytoplasmic dynein showed no significant change in mRNA expression during cellular aging. Cell growth arrest by serum starvation, contact inhibition, or gamma-irradiation did not induce the DNCI1 mRNA, suggesting its specific role in cellular senescence. The DNCI1 gene is on the long arm of chromosome 7 where tumor suppressor genes and a senescence-inducing gene for a group of immortal cell lines (complementation group D) are mapped. This is the first report that links a component of molecular motor complex to cellular senescence, providing a new insight into molecular mechanisms of cellular senescence.