Correlative evidence supports telomere erosion as a major driver of aging decline, yet this is challenged by mammals such as laboratory mice Mus musculus , whose telomeres do not reach a critical limit during normal aging. Telomere length is also not predictive of aging deterioration in mice Rudolph et al. Metabolic dysfunction relates to aging at the organismal and molecular level. Multiple studies have demonstrated that caloric restriction can retard the aging decline Mitchell et al.
Molecularly, pathways fine-tuning metabolic regulation, such as the mTOR or insulin pathway, have also been linked to increased health span and life span Selman et al. The connection between autophagy and senescence is complex; although there is an increase in autophagy during senescence that serves to regulate SASP production Narita et al.
Sirtuins constitute another molecular link between metabolism and senescence. Sirtuins are ribosyltransferases with a wide array of functions, such as metabolism regulation and DNA repair Houtkooper et al.
Their role in senescence is antagonistic; SIRT1 deacetylates p53, promotes its degradation Solomon et al. In addition to these forms of damage, general stress is sensed by other mechanisms such as activation of MAPK p38 or induction of p16 INK4a. These pathways are up-regulated in response to oxidative stress, DNA damage, telomere attrition, or oncogene activation. Overall, it is likely that the accumulation of senescent cells during aging reflects a gradual increase of different types of damage in different tissues.
Despite the multifaceted nature of senescence, the induction of stable growth arrest is the defining characteristic of senescence. Moreover, stable arrest is paramount to halt the propagation of dysfunctional cells.
Senescence inducers such as telomeric attrition and oncogenic or oxidative stress cause DNA damage. Although transient increases in p53 levels can enact a quiescent state and activate DNA repair processes, during senescence, there is a sustained induction of p53 Salama et al. This is a result of damage occurring in repair-resistant regions of the genome known as DNA segments with chromatin alterations reinforcing senescence, such as telomeres Rodier et al.
Given the key roles of p53, additional regulatory layers exist. Recently, the interaction between Forkhead box protein O4 FOXO4 and p53 has been shown to play an important role in modulating p53 localization and transcriptional activity during senescence Baar et al.
Interestingly FOXO transcription factors regulate aging, with FOXO activity in Drosophila melanogaster leading to delayed aging in response to disrupted protein homeostasis and oxidative stress Demontis and Perrimon, Given this unusual concentration of three tumor suppressors in barely 35 kb, this locus plays a key regulatory role and is frequently mutated in cancer Gil and Peters, ; Kim and Sharpless, However, most of these are found in noncoding regions, and the precise mechanism of action is unclear.
In particular, p16 INK4a is considered an aging biomarker. With exceptions such as during senescence-induced during development , p16 INK4a is also one of the best markers of senescence.
An analysis of the pathways regulating p16 INK4a shows coincidences with those controlling development. This has been argued to formulate the theory that aging might be driven by gradual functional decay of developmental pathways Martin et al. Besides growth arrest, the production of a complex mixture of secreted factors, termed the SASP or senescence-messaging secretome, is the most relevant phenotypic program implemented in senescent cells.
The specific combination of secreted factors is thought to depend on the cell type and the senescent inducer. However, many of the key effectors of the SASP and its regulatory mechanism seemed to be shared.
DNA damage Rodier et al. There are additional layers of SASP regulation. There is also a global remodeling of enhancers in senescent cells, and the recruitment of BRD4 to superenhancers adjacent to SASP genes is needed for their induction Tasdemir et al. The SASP is responsible for many of the positive and negative functions attributed to senescent cells Fig. One of the major functions of the SASP is to recruit the immune system to eliminate senescent cells.
In general terms, the effects are positive. During tumor initiation, SASP-mediated immune recruitment acts as an extrinsic tumor suppressor mechanism Xue et al. In contrast, SASP-mediated recruitment of immature myeloid cells has immune suppressive effects on prostate and liver cancer Di Mitri et al. In addition, the SASP can stimulate tumorigenesis by promoting angiogenesis e.
Specific components of the SASP have other physiological functions, such as contributing to fibrotic tissue remodeling, whereby matrix metalloproteinases MMPs contribute to degrade fibrotic plaques in the ECM that may be beneficial in the context of liver fibrosis and wound healing Krizhanovsky et al.
Functions of the SASP. The SASP mediates many of the cell-extrinsic functions of senescent cells. Among those it reinforces several aspects of senescence including growth arrest and the SASP itself via an autocrine loop. The SASP also recruits immune cells, such as macrophages, neutrophils, and natural killer NK cells to phagocytose and eliminate the senescent cell.
Recently, it has been postulated that senescent cells accumulating in response to tissue damage can also promote stemness and reprogramming Ritschka et al. However, how this fits with the increased number of senescent cells but decreased stemness potential observed during aging is unclear. On the other hand, factors secreted by senescent cells can reinforce the senescent phenotype, potentially exacerbating senescence during aging.
Moreover, senescent cells can also induce a so-called paracrine senescence response Acosta et al. This autocrine reinforcement or paracrine transmission of senescence could potentially explain some of the detrimental effects of aberrant accumulation of senescent cells during aging. During aging, the SASP is thought to be partially responsible for persistent chronic inflammation, also known as inflammaging, that contributes to multiple age-related phenotypes.
This contribution of SASP in inflammaging is beginning to be investigated using senolytic models. The direct elimination of senescent cells in aged kidney Baker et al. It would be pertinent in future aging therapies to understand how specific aspects of the SASP contribute to the deterioration or protection of tissues. Although the contribution of senescence to aging has been long suspected, only recently has the connection been confirmed.
This has been made possible by the use of molecular biomarkers of senescence and the establishment of novel genetic models to study the role of senescent cells in vivo. Furthermore, p16 INK4a accumulates during aging.
Its knockout also mitigates functional decline and proliferative exhaustion upon HSC transplantation Janzen et al. The possible detrimental effects cause by p16 INK4a overexpression may be outweighed by their clear tumor suppressive benefits, with a threefold reduction in tumor incidence Matheu et al. One of the biggest hindrances to investigating senescence in vivo has been the lack of robust, consistent markers.
However, these may yield mixed results. The use of additional senescence markers, such as lipofuscin, which accumulates in the cytoplasm of senescent cells, could be applied to bridge this gap Sharpless and Sherr, Another useful tool that has emerged is the use of bioluminescent senescence reporters.
With the advent of p16 INK4a -LUC mice expressing a luciferase reporter under the control of a p16 INK4a promoter, there is now confirmation that multiple tissues show an exponential age-related increase in p16 INK4a expression that correlates with higher levels of proinflammatory factors or SASP components Yamakoshi et al. Establishing causality of a gene in diseases such as cancer is usually a matter of generating appropriate knockout or overexpression mouse models.
Seminal studies by Baker et al. The elimination of senescent cells improved several age-associated conditions, delayed tumor formation, and ameliorated the side effects of chemotherapy Baker et al. These studies have finally confirmed that senescence causes, or at least contributes to, aging. There is clear evidence suggesting how the SASP participates in the clearance of premalignant cells or contributes to tumor progression Kang et al.
The detrimental role for chronic inflammation during aging is further supported by clinical data Libby, ; Brunt et al. Aging phenotypes such as frailty Soysal et al. The increased levels of chronic inflammation in these instances are collectively termed inflammaging Franceschi and Campisi, The reason for such increases in levels of proinflammatory molecules remains unknown.
Although accumulated damage and lifelong antigenic load may undoubtedly contribute to this increase in inflammation, senescence may also help mediate inflammaging. This contribution of senescence to inflammaging may be via several coalescing effects, the first being through the SASP.
As damage accumulates in tissues, the number of senescent cells and their SASP also increases. This process is usually resolved by clearance of the senescent cells by the immune system Kang et al.
In aged individuals, however, senescence also contributes to a decline in immune function termed immunosenescence, thereby compromising the clearance of senescent cells and exacerbating inflammation. Emerging studies using genetic systems or drugs ablating senescent cells suggest that the elimination of senescent cells reduces inflammation across tissues Baker et al. Future studies will need to establish the causal link between the SASP, chronic inflammation, and tissue dysfunction. These might require the generation of novel mouse models that take advantage of our knowledge on SASP regulation.
Now that a general causative role for senescence during aging has been established, the next step is to identify how senescence contributes to different age-related pathologies such as glaucoma Liton et al. Thanks to the use of senolytic drugs and genetic models for senescence ablation, we are progressing quickly in that task. Involvement of senescence in disease. Establishment of robust biomarkers of senescence, usage of genetic knockout models and senolytic models are expanding our knowledge on the age-related diseases in which senescence plays a role.
Senescence is a strong tumor suppressor mechanism that limits cancer initiation through both cell-intrinsic Collado and Serrano, and cell-extrinsic mechanisms Kang et al. Senescent cells can contribute to tumor progression by enhancing the proliferative potential of cancer cells Krtolica et al. Therefore, the increased numbers of senescent cells present in aged tissues could contribute to the increased incidence of cancer with age.
Supporting this, a delayed onset in tumor formation is observed when senescent cells are eliminated Baker et al. Senolytic therapy also reduces the incidence of metastasis, the leading cause of cancer-related deaths Demaria et al. Aged individuals often display a reduced glomerular filtration rate and cortical volume that can result in glomerulosclerosis and nephron atrophy, both of which are associated with increased expression of p16 INK4a and p53 Melk et al.
Senescence has detrimental effects in most renal diseases analyzed Sturmlechner et al. Ablation of senescent cells protects against glomerulosclerosis and improves kidney function in aged mice Baker et al. One of the largest risk factors for the development of type 2 diabetes is age. Fibrosis is a pathological condition whereby tissue accumulates ECM proteins such as collagen, resulting in tissue scarification, usually in response to damage.
Senescence appears to have both beneficial and detrimental roles during fibrosis and wound healing. The detrimental nature of senescence in IPF was recently demonstrated using senolytics. Elimination of senescent fibroblasts in a mouse model of lung fibrosis reduced expression of profibrotic SASP components and improved pulmonary function Schafer et al.
Cirrhosis is the pathological outcome from liver fibrosis and nonalcoholic fatty liver disease, which in turn is a result of hepatic steatosis, the abnormal accumulation of lipids in hepatocytes Pellicoro et al.
Study Findings. Metastatic Cancer Research. Intramural Research. Extramural Research. Cancer Research Workforce. Partners in Cancer Research. What Are Cancer Research Studies. Research Studies. Get Involved. Cancer Biology Research. Cancer Genomics Research. Research on Causes of Cancer. Cancer Prevention Research. Cancer Treatment Research. Cancer Health Disparities. Childhood Cancers Research. Global Cancer Research. Cancer Research Infrastructure. Clinical Trials. Frederick National Laboratory for Cancer Research.
Bioinformatics, Big Data, and Cancer. Annual Report to the Nation. Research Advances by Cancer Type. Stories of Discovery. Milestones in Cancer Research and Discovery. Biomedical Citizen Science. Director's Message. Budget Proposal. Stories of Cancer Research. Driving Discovery. Highlighted Scientific Opportunities. Research Grants. While the full effect of NF-kB inhibition remains untested, it seems likely that with such a central role in cell signaling and inflammation, inhibition is likely to be context and cell dependent but has been proposed as a potential senolytic target Salminen et al.
Drugs which have been considered for this purpose include antioxidants and inhibitors of the NF-kB pathway Nelson et al. Genetic reduction of NF-kB in a fast aging mouse was shown to delay the onset of several age-related pathologies. As is the case with genetic depletion, treated mice showed a delay in the onset of the majority of aging symptoms Tilstra et al. Furthermore, calorie restriction CR is widely recognized to extend longevity and in mice reduces senescent cell burden Colman et al.
Thus, CR; a known mediator of improved healthspan and a known senolytic approach appears to function at least in part through NF-kB inhibition. The SASP is rich in pro-inflammatory cytokines and chemokines. Consistent with this, old rats have increased numbers of senescent pre-adipocytes and have higher levels of activated JAK1 and JAK2 Xu et al.
Using this approach, PTRP1 was identified as a factor mediating the inflammatory effects of the SASP with blockade inhibiting the pro-inflammatory and tumorigenic properties of senescent cells in the liver Georgilis et al.
Indeed, sirolimus also known as rapamycin ; a drug well known to nephrologists, has been shown experimentally to inhibit the senescence phenotype Gu et al. Given the importance of senescent cells in wound healing Demaria et al. Similarly, metformin; another well-known drug with over 60 years' worth of clinical use is now being considered as an encouraging senostatic candidate.
Metformin targets multiple intracellular signaling pathways closely associated with the development of aging, such as inflammation, cellular survival, stress defence, autophagy, and protein synthesis. An alternative option is to consider manipulating individual SASP components. In a phase 2 trial in patients with idiopathic pulmonary fibrosis, pamrevlumab, a fully recombinant human monoclonal antibody against CTGF, attenuated the decline in lung function and reduced the proportion of patients with disease progression compared to placebo Richeldi et al.
Fundamental questions remain surrounding the pathways regulating senescence, their roles in tissue aging and dysfunction, and their potential therapeutic use:. Our understanding of senescent cells in vivo remains incomplete. Global knockout models and generic P16 INK4A driven approaches have been informative, but have caveats as described.
Such models should allow a deeper characterization of the pathways to senescence at single cell level; i. As described, senescence is important for wound healing Krizhanovsky et al. With respect to renal injury, it is likely that optimal recovery requires the induction of senescent cells most likely of different cell lineages at key time-points.
Thus, a delicate balance is required to promote adaptive rather than maladaptive repair. The specific identity and roles of these cells in renal repair versus development of fibrosis remain unknown at present and it is imperative that we understand this to deliver optimal senolytic therapies.
Over the last five years depletion of senescent cells in animal models has demonstrated striking results across multiple tissues, organs and at whole animal level and this continues to inspire the development and refinement of therapy. However, as yet, their efficacy and safety has not been extensively tested in humans. Multiple early stage clinical trials are underway and early reports are encouraging Hickson et al.
These include NCT, a trial which tests dasatinib and quercetin as senolytics in diabetic patients with chronic kidney disease, NCT which will test the same agents in the modulation of progression of Alzheimer's disease and NCT comparing dasatinib, quercetin and fisetin on senescence levels and bone mineral density in elderly women.
It is to be hoped that in the next five years many of these questions will be answered. Current and future studies will undoubtedly broaden our knowledge of the key pathogenic mechanisms of senescent cells and hence permit refined therapies to deplete senescent cells in a targeted manner.
It may also be possible to target the metabolic alterations present with senescence to deliver selective therapies to limit senescent cell survival. Finally, the presence of clinically licenced compounds with the ability to restrain the deleterious effects of senescence via inhibition of SASP release may allow these to be the first agents to transition from experimental models to clinical use.
MD planned the study and wrote and revised the text. DB planned the study and wrote the text. JH reviewed and revised the text. DF planned the study, designed the figures, and reviewed and revised the text. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The J. You can also search for this author in PubMed Google Scholar. Li-Fraumeni syndrome. Fabrizio d'Adda di Fagagna's homepage. A tissue in which cell proliferation is important for tissue repair or regeneration. Renewable tissues typically contain, but sometimes recruit, mitotic cells upon injury or cell loss. The hypothesis that genes or processes that were selected to benefit the health and fitness of young organisms can have unselected deleterious effects that manifest in older organisms and thereby contribute to ageing.
A cell that has the ability to proliferate. In vivo , mitotic cells often exist in a reversible growth-arrested state that is termed quiescence or G0 phase, but such cells can be stimulated to proliferate in response to appropriate physiological signals.
A reversible non-dividing state from which cells can be stimulated to proliferate in response to physiological signals. The combination of changes in cell behaviour, structure and function that occur upon cellular senescence.
For most cell types, these changes include an essentially irreversible growth arrest, resistance to apoptosis and many alterations in gene expression. A gene that contributes to the malignant transformation of cells.
Oncogenes can be cellular or viral in origin. Cellular oncogenes are usually mutant or overexpressed forms of normal cellular genes. Viral oncogenes can also originate from cellular genes, acquiring mutations during viral capture, but they can also be distinctly viral in origin. The DNA and complex of associated proteins that determine the accessibility of large DNA regions to the transcription machinery and other large protein complexes.
Chromatin that is in a closed conformation and hence inaccessible. Also termed silent or inactive chromatin. Chromatin probably exists in many forms between the extremes of euchromatin and heterochromatin. Reprints and Permissions. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8, — Download citation. Issue Date : September Anyone you share the following link with will be able to read this content:.
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