DNA damage response and cellular senescence in tissues of aging mice

The impact of cellular senescence onto aging of organisms is not fully clear, not at least because of the scarcity of reliable data on the mere frequency of senescent cells in aging tissues. Activation of a DNA damage response including formation of DNA damage foci containing activated H2A.X (γ-H2A.X) at either uncapped telomeres or persistent DNA strand breaks is the major trigger of cell senescence. Therefore, γ-H2A.X immunohistochemistry (IHC) was established by us as a reliable quantitative indicator of senescence in fibroblasts in vitro and in hepatocytes in vivo and the age dependency of DNA damage foci accumulation in ten organs of C57Bl6 mice was analysed over an age range from 12 to 42 months. There were significant increases with age in the frequency of foci-containing cells in lung, spleen, dermis, liver and gut epithelium. In liver, foci-positive cells were preferentially found in the centrilobular area, which is exposed to higher levels of oxidative stress. Foci formation in the intestine was restricted to the crypts. It was not associated with either apoptosis or hyperproliferation. That telomeres shortened with age in both crypt and villus enterocytes, but telomeres in the crypt epithelium were longer than those in villi at all ages were confirmed by us. Still, there was no more than random co-localization between γ-H2A.X foci and telomeres even in crypts from very old mice, indicating that senescence in the crypt enterocytes is telomere independent. The results suggest that stress-dependent cell senescence could play a causal role for aging of mice.     

Emerging roles of extracellular vesicles in cellular senescence and aging

Cellular senescence is a cellular program that prevents the proliferation of cells at risk of neoplastic transformation. On the other hand, age‐related accumulation of senescent cells promotes aging at least partially due to the senescence‐associated secretory phenotype, whereby cells secrete high levels of inflammatory cytokines, chemokines, and matrix metalloproteinases. Emerging evidence, however, indicates that extracellular vesicles (EVs) are important mediators of the effects of senescent cells on their microenvironment. Senescent cells secrete more EphA2 and DNA via EVs, which can promote cancer cell proliferation and inflammation, respectively. Extracellular vesicles secreted from DNA‐damaged cells can also affect telomere regulation. Furthermore, it has now become clear that EVs actually play important roles in many aspects of aging. This review is intended to summarize these recent progresses, with emphasis on relationships between cellular senescence and EVs.     

端粒、端粒酶与细胞衰老

端粒和端粒酶是现代生物学研究的热点,端粒的缺失与细胞的衰老,端粒酶的活性与细胞的老化及癌化均有密切的关系。章综述了端粒和端粒酶的结构和功能,及其与细胞衰老的关系,并在此基础之上展望了端粒酶在抗衰老、抑制肿瘤等方面的应用。     

Fat tissue,aging, and cellular senescence

Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age‐related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span. Fat cells turn over throughout the life span. Fat cell progenitors, preadipocytes, are abundant, closely related to macrophages, and dysdifferentiate in old age, switching into a pro‐inflammatory, tissue‐remodeling, senescent‐like state. Other mesenchymal progenitors also can acquire a pro‐inflammatory, adipocyte‐like phenotype with aging. We propose a hypothetical model in which cellular stress and preadipocyte overutilization with aging induce cellular senescence, leading to impaired adipogenesis, failure to sequester lipotoxic fatty acids, inflammatory cytokine and chemokine generation, and innate and adaptive immune response activation. These pro‐inflammatory processes may amplify each other and have systemic consequences. This model is consistent with recent concepts about cellular senescence as a stress‐responsive, adaptive phenotype that develops through multiple stages, including major metabolic and secretory readjustments, which can spread from cell to cell and can occur at any point during life. Senescence could be an alternative cell fate that develops in response to injury or metabolic dysfunction and might occur in nondividing as well as dividing cells. Consistent with this, a senescent‐like state can develop in preadipocytes and fat cells from young obese individuals. Senescent, pro‐inflammatory cells in fat could have profound clinical consequences because of the large size of the fat organ and its central metabolic role.     

The potential role of senescence in limiting fibrosis caused by aging

Fibrosis-related diseases carry with them a high mortality rate and their morbidity increases with age. Recent findings indicate that induced senescence in myofibroblasts can limit or reduce myocardial fibrosis, cirrhosis, and idiopathic pulmonary fibrosis, while also accelerating wound healing. However, more senescent cells are accumulated as organisms age, which exacerbates aging-related diseases. These two contradictory theories inspired us to summarize papers on the restrictive effect of senescence on fibrosis and to input the key findings into simple software that we developed to assist with data organization and presentation. In this review, we illustrate that senescent cells secrete more matrix metalloproteinases to solubilize excess collagen, while chemokines and cytokines activate immune cells to eliminate senescent cells. In the elderly, it is perhaps more effective to limit fibrosis by inducing myofibroblast senescence and then removing senescent cells that are not cleared via normal mechanisms by antisenescence therapies.     

Increased polyploidy in aortic vascular smooth muscle cells during aging is marked by cellular senescence

We previously reported that the frequency of polyploid aortic vascular smooth muscle cells (VSMC) serves as a biomarker of aging. Cellular senescence of somatic cells is another marker of aging that is characterized by the inability to undergo cell division. Here, we examined whether polyploidy is associated with the development of cellular senescence in vivo. Analysis of aortic tissue preparations from young and old Brown Norway rats showed that expression of senescence markers such as p16(INK4a) and senescence-associated beta-galactosidase activity are detected primarily in the old tissues. VSMC from p16(INK4a) knockout and control mice display similar levels of polyploid cells. Intriguingly, senescence markers are expressed in most, but not all, polyploid VSMC. Moreover, the polyploid cells exhibit limited proliferative capacity in comparison to their diploid counterparts. This study is the first to demonstrate in vivo that polyploid VSMC adopt a senescent phenotype.     

Cpne7 deficiency induces cellular senescence and premature aging of dental pulp

Once tooth development is complete, odontoblasts and their progenitor cells in the dental pulp play a major role in protecting tooth vitality from external stresses. Hence, understanding the homeostasis of the mature pulp populations is just as crucial as understanding that of the young, developing ones for managing age-related dentinal damage. Here, it is shown that loss of Cpne7 accelerates cellular senescence in odontoblasts due to oxidative stress and DNA damage accumulation. Thus, in Cpne7-null dental pulp, odontoblast survival is impaired, and aberrant dentin is extensively formed. Intraperitoneal or topical application of CPNE7-derived functional peptide, however, alleviates the DNA damage accumulation and rescues the pathologic dentin phenotype. Notably, a healthy dentin-pulp complex lined with metabolically active odontoblasts is observed in 23-month-old Cpne7-overexpressing transgenic mice. Furthermore, physiologic dentin was regenerated in artificial dentinal defects of Cpne7-overexpressing transgenic mice. Taken together, Cpne7 is indispensable for the maintenance and homeostasis of odontoblasts, while promoting odontoblastic differentiation of the progenitor cells. This research thereby introduces its potential in oral disease-targeted applications, especially age-related dental diseases involving dentinal loss.     

Exploring the emerging bidirectional association between inflamm-aging and cellular senescence in organismal aging and disease

There is strong evidence that most individuals in the elderly population are characterized by inflamm-aging which refers to a subtle increase in the systemic pro-inflammatory environment and impaired innate immune activation. Although a variety of distinct factors are associated with the progression of inflamm-aging, emerging research is demonstrating a dynamic relationship between the processes of cellular senescence and inflamm-aging. Cellular senescence is a recognized factor governing organismal aging, and through a characteristic secretome, accumulating senescent cells can induce and augment a pro-inflammatory tissue environment that provides a rationale for immune system-independent activation of inflamm-aging and associated diseases. There is also accumulating evidence that inflamm-aging or its components can directly accelerate the development of senescent cells and ultimately senescent cell burden in tissues in a likely vicious inflammatory loop. The present review is intended to describe the emerging senescence-based molecular etiology of inflamm-aging as well as the dynamic reciprocal interactions between inflamm-aging and cellular senescence. Therapeutic interventions concurrently targeting cellular senescence and inflamm-aging are discussed and limitations as well as research opportunities have been deliberated. An effort has been made to provide a rationale for integrating inflamm-aging with cellular senescence both as an underlying cause and therapeutic target for further studies.     

Loss of Pla2r1 decreases cellular senescence and age-related alterations caused by aging and Western diets

Cellular senescence is induced by many stresses including telomere shortening, DNA damage, oxidative, or metabolic stresses. Senescent cells are stably cell cycle arrested and they secrete many factors including cytokines and chemokines. Accumulation of senescent cells promotes many age-related alterations and diseases. In this study, we investigated the role of the pro-senescent phospholipase A2 receptor 1 (PLA2R1) in regulating some age-related alterations in old mice and in mice subjected to a Western diet, whereas aged wild-type mice displayed a decreased ability to regulate their glycemia during glucose and insulin tolerance tests, aged Pla2r1 knockout (KO) mice efficiently regulated their glycemia and displayed fewer signs of aging. Loss of Pla2r1 was also found protective against the deleterious effects of a Western diet. Moreover, these Pla2r1 KO mice were partially protected from diet-induced senescent cell accumulation, steatosis, and fibrosis. Together these results support that Pla2r1 drives several age-related alterations, especially in the liver, arising during aging or through a Western diet.     

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.     

SIRTain regulators of premature senescence and accelerated aging

The sirtuin proteins constitute class III histone deacetylases (HDACs). These evolutionarily conserved NAD⁺-dependent enzymes form an important component in a variety of cellular and biological processes with highly divergent as well as convergent roles in maintaining metabolic homeostasis, safeguarding genomic integrity, regulating cancer metabolism and also inflammatory responses. Amongst the seven known mammalian sirtuin proteins, SIRT1 has gained much attention due to its widely acknowledged roles in promoting longevity and ameliorating age-associated pathologies. The contributions of other sirtuins in the field of aging are also gradually emerging. Here, we summarize some of the recent discoveries in sirtuins biology which clearly implicate the functions of sirtuin proteins in the regulation of premature cellular senescence and accelerated aging. The roles of sirtuins in various cellular processes have been extrapolated to draw inter-linkage with anti-aging mechanisms. Also, the latest findings on sirtuins which might have potential effects in the process of aging have been reviewed.     

Recent advances in cellular senescence, cancer and aging

How much do we know about the biology of aging from cell culture studies? Most normal somatic cells have a finite potential to divide due to a process termed cellular or replicative senescence. A growing body of evidence suggests that senescence evolved to protect higher eukaryotes, particularly mammals, from developing cancer. We now know that telomere shortening, due to the biochemistry of DNA replication, induces replicative senescence in human cells. However, in rodent cells, replicative senescence occurs despite very long telomeres. Recent findings suggest that replicative senescence is just the tip of the iceberg of a more general process termed cellular senescence. It appears that cellular senescence is a response to potentially oncogenic insults, including oxidative damage. In young organisms, growth arrest by cell senescence suppresses tumor development, but later in life, due to the accumulation of senescent cells which secret factors that can disrupt tissues during aging, cellular senescence promotes tumorigenesis. Therefore, antagonistic pleiotropy may explain in part, if not in whole, the apparently paradoxical effects of cellular senescence, though this still remains an open question.     

Integrating cellular senescence with the concept of damage accumulation in aging: Relevance for clearance of senescent cells

Understanding the aging process and ways to manipulate it is of major importance for biology and medicine. Among the many aging theories advanced over the years, the concept most consistent with experimental evidence posits the buildup of numerous forms of molecular damage as a foundation of the aging process. Here, we discuss that this concept integrates well with recent findings on cellular senescence, offering a novel view on the role of senescence in aging and age‐related disease. Cellular senescence has a well‐established role in cellular aging, but its impact on the rate of organismal aging is less defined. One of the most prominent features of cellular senescence is its association with macromolecular damage. The relationship between cell senescence and damage concerns both damage as a molecular signal of senescence induction and accelerated accumulation of damage in senescent cells. We describe the origin, regulatory mechanisms, and relevance of various damage forms in senescent cells. This view on senescent cells as carriers and inducers of damage puts new light on senescence, considering it as a significant contributor to the rise in organismal damage. Applying these ideas, we critically examine current evidence for a role of cellular senescence in aging and age‐related diseases. We also discuss the differential impact of longevity interventions on senescence burden and other types of age‐related damage. Finally, we propose a model on the role of aging‐related damage accumulation and the rate of aging observed upon senescent cell clearance.     

HuR and post-transcriptional regulation in vascular aging

HuR(ELAV11(embryonic lethal,abnormal vision)-like 1),a ubiquitously expressed member of the ELAV-like RNA-binding protein family,has been shown to regulate the stability and translation of mRNAs that encode factors regulating cellular senescence,thereby impacting on aging.In this review,we discuss the current knowledge of HuR’s role in vascular cell senescence and vascular aging.     

On the evolution of cellular senescence

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).     

Small molecule compounds that induce cellular senescence

To date, dozens of stress‐induced cellular senescence phenotypes have been reported. These cellular senescence states may differ substantially from each other, as well as from replicative senescence through the presence of specific senescence features. Here, we attempted to catalog virtually all of the cellular senescence‐like states that can be induced by low molecular weight compounds. We summarized biological markers, molecular pathways involved in senescence establishment, and specific traits of cellular senescence states induced by more than fifty small molecule compounds.     

Telomere, DNA damage, and oxidative stress in stem cell aging

"Stem cell aging" is a novel concept that developed together with the advances of stem cell biology, especially the sophisticated prospectively isolation and characterization of multipotent somatic tissue stem cells. Although being immortal in principle, stem cells can also undergo aging processes and potentially contribute to organismal aging. The impact of an age-dependent decline of stem cell function weighs differently in organs with high or low rates of cell turnover. Nonetheless, most of the organ systems undergo age-dependent loss of homeostasis and functionality, and emerging evidence showed that this has to do with the aging of resident stem cells in the organ systems. The mechanisms of stem cell aging and its real contribution to human aging remain to be defined. Many antitumor mechanisms protect potential malignant transformation of stem cell by inducing apoptosis or senescence but simultaneously provoke stem cell aging. In this review, we try to discuss several concept of stem cell aging and summarize recent progression on the molecular mechanisms of stem cell aging.     

Targeting the redox system for cardiovascular regeneration in aging

Cardiovascular aging presents a formidable challenge, as the aging process can lead to reduced cardiac function and heightened susceptibility to cardiovascular diseases. Consequently, there is an escalating, unmet medical need for innovative and effective cardiovascular regeneration strategies aimed at restoring and rejuvenating aging cardiovascular tissues. Altered redox homeostasis and the accumulation of oxidative damage play a pivotal role in detrimental changes to stem cell function and cellular senescence, hampering regenerative capacity in aged cardiovascular system. A mounting body of evidence underscores the significance of targeting redox machinery to restore stem cell self-renewal and enhance their differentiation potential into youthful cardiovascular lineages. Hence, the redox machinery holds promise as a target for optimizing cardiovascular regenerative therapies. In this context, we delve into the current understanding of redox homeostasis in regulating stem cell function and reprogramming processes that impact the regenerative potential of the cardiovascular system. Furthermore, we offer insights into the recent translational and clinical implications of redox-targeting compounds aimed at enhancing current regenerative therapies for aging cardiovascular tissues.