Senescence pdf

Senescence can in turn drive the consequential aging hallmarks in response to damage: stem cell exhaustion and chronic inflammation.

Other responses to damage, such as proteostatic dysfunction and nutrient signaling disruption, are also integrally linked with the senescence response. Senescence also influences the integrative aging hallmarks.

Somatic multipotent stem cells facilitate tissue homeostasis; for example, hematopoietic stem cells HSCs renew the blood system. Stem cell exhaustion occurs with age, and the consequent decline in stem cell functionality and their capacity for renewal leads to tissue deterioration. For example, HSCs display a decreased success rate of transplantation when isolated from elderly patients Kollman et al.

This decline correlates with increased numbers of senescent HSCs Chang et al. Somatic stem cell decline is not limited to high-turnover tissues. Neural stem cells NSCs experience reduced functionality, with limited neurogenesis capacity with age. This is marked by a twofold reduction in NSC numbers and a decreased proliferation, which correlates with increased expression of senescence markers in the regions where NSCs reside Molofsky et al.

Mesenchymal stem cells Raggi and Berardi, and their descendants, satellite cells Shefer et al. This may have an impact in age-associated pathologies such as sarcopenia, cachexia, osteoporosis, and osteoarthritis Fried et al. Altered intracellular communication is another of the integrative hallmarks of aging. This detrimental role of inflammation is supported by inflammatory markers such as interleukin-1 IL-1 and IL-6 acting as prognostic markers for diseases such as type 2 diabetes Dandona et al.

Aging influences a broad range of disease etiologies. Therefore, targeting the underlying aging machinery may provide broad-spectrum protection against many pathologies. Senescence is cellular program that induces a stable growth arrest accompanied by distinct phenotypic alterations, including chromatin remodeling, metabolic reprogramming, increased autophagy, and the implementation of a complex proinflammatory secretome Kuilman et al.

These complex changes to the cell largely serve to implement various aspects of senescence such as growth arrest and the senescence secretome. Despite the many facets of senescence, stable growth arrest is its defining characteristic. A permanent arrest is effective to ensure that damaged or transformed cells do not perpetuate their genomes. Pathways regulating senescence-mediated arrest. Historically, senescence was first identified by Hayflick and Moorhead during serial passage of human fibroblasts.

The limit to proliferation that senescence imposes was hypothesized as a barrier to cancer initiation. Senescence is indeed a powerful mechanism of tumor suppression Collado et al. In adult tissues, senescence is triggered primarily as a response to damage, allowing for suppression of potentially dysfunctional, transformed, or aged cells. The aberrant accumulation of senescent cells with age results in potential detrimental effects. In balance, although senescence is a biologically necessary process, it may come at a cost.

The early research of Hayflick and Moorhead hinted at a relationship between senescence and aging, but the consequent discovery that senescent cells accumulate in aged tissues has substantiated the hypothesis that senescence itself can drive aging.

In adult tissues, senescence is engaged in response to different types of damage. One of the insults causing senescence is damage of the telomeres, highly repetitive DNA structures located at the end of chromosomes. Telomeres are protected by a multiprotein complex known as shelterin. By coating the telomere, shelterin prevents the activation of a DNA damage response, thereby preventing end-to-end chromosome fusions that would result in a telomere crisis Palm and de Lange, The end-replication problem is a consequence of the inability of DNA polymerases to synthesize DNA without a template, which occurs at telomeres.

This results in telomeres that shorten progressively with each cell cycle division. Embryonic tissues circumvent this erosion by expressing telomerase, a ribonucleoprotein complex that serves to concatenate DNA to the ends of chromosomes, thus providing a template for DNA synthesis Nandakumar and Cech, Repeated cell division in adult tissues that lack telomerase, however, results in progressive erosion of DNA, reduced shelterin binding, and senescence.

As an organism ages, cells accumulate more divisions. This results in increased telomere erosion and senescence. But the extent to which telomere erosion drives senescence during aging and contributes to the aging process itself remains unknown. Supporting the causative role of telomere erosion in aging, deletion of telomerase in mice eventually results in premature aging Lee et al.

This phenotype can be rescued by transient activation of telomerase reverse transcription expression in mice using a telomerase reverse transcription estrogen receptor construct. Cells isolated from these mice proliferate normally in vitro, and deterioration in multiple tissues is reduced Jaskelioff et al. This evidence correlates with studies showing that fibroblasts or T cells derived from centenarians reset their telomeres, which results in rejuvenation and sustained proliferation Lapasset et al.

Similarly, stimulation of T cells derived from serially transplanted HSCs results in telomerase expression and rejuvenation Allsopp et al. Shortened telomeres are associated with many pathologies such as liver cirrhosis Rudolph, and correlate with an increase in mortality in people older than 60 years Cawthon et al.

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.

Senescence is associated with liver fibrosis Kim et al. The risk of developing nonalcoholic fatty liver disease increases with age Hardy et al.

The role of senescence in the liver is complex, however, because knocking out p53 or p16 INK4a increases liver fibrosis Krizhanovsky et al. Moreover, senescent hepatic stellate cells down-regulate collagen and up-regulate MMPs and cytokines that could remodel fibrotic plaques and recruit macrophages Krizhanovsky et al. The risk of developing atherosclerosis and cardiomyopathy and their respective conditions, coronary heart disease and heart failure, increases with age.

In the case of atherosclerosis, the role of senescence has been confirmed using senolytic models Childs et al. Ablation of senescent cells improved the stability of plaques and reduced both the incidence and progression of plaque formation. Senescent cells were initially identified in atherosclerosis in vascular smooth muscle cells at the site of the plaque Uryga and Bennett, Cardiomyocyte atrophy is one of the underlying causes of myocardial infarction in the elderly Niccoli and Partridge, It is unclear how ablation of senescent cells protects against cardiomyocyte hypertrophy in aged mice and provides resistance to cardiac stress Baker et al.

Lifelong wear and tear on ligaments is a significant risk factor for the development of arthritis. Failure of chondrocytes to produce cartilage results in degradation of joints and immobilization. Expression of p16 INK4a in these cells correlates with severity and progression of the disease Price et al. Moreover, when mice were subjected to an acute trauma to model osteoarthritis, senescent cells accumulated in the site of the injury Kuyinu et al.

Clearance of these senescent cells using senolytics resulted in the increased functionality of the remaining chondrocytes with rejuvenation of cartilage soon after Jeon et al. One of the primary risk factors for complications in end-of life care is infection.

The inability of the body to raise a response to immune offenses is caused by a functional decline in HSCs. The accumulation of senescent HSCs with age contributes to immune decline and senescence bypass allows for stem cell rejuvenation.

Interestingly, the removal of these cells restored the functionality of HSCs and increased myeloid, B, and T cell numbers in transplant experiments Chang et al.

Muscle stem cells MuSCs undergo a decline in their ability to differentiate and facilitate repair of muscle tissue, which is hypothesized to be the underlying cause of age-dependent muscle wasting or sarcopenia. MuSCs are quiescent unless stimulated to repair muscle Gopinath and Rando, Loss of adiposity and loss of muscle mass in aged individuals are primary contributors to age-dependent wastage or cachexia.

Removal of senescent cells from mice leads to increased adiposity and prevents mass loss in aged mice Baker et al. Recently it has been shown that bypass of senescence or senolysis restores adipose beiging and adipogenesis and improves metabolic function in aged mice Xu et al.

This suggests that senescent cells prevent adipocyte differentiation and contribute to an age-dependent loss of adaptive thermogenic capacity and metabolic dysfunction. Because of the detrimental nature of senescence in the etiology of numerous diseases, disrupting or preventing senescence can delay health decline during aging.

Inhibition of p38, disruption of p53 and p16, or lengthening of telomeres have all been shown to benefit aging phenotypes but carry a major caveat, as they can increase the incidence of cancer Sharpless et al.

The selective elimination of senescent cells has revealed to be a safer route to target senescence during aging. ABT, otherwise known as navitoclax, is a BH3 mimetic that blocks the interaction between antiapoptotic BCL-2 proteins and their targets, thereby releasing the brakes on the cell death machinery, and has been used to treat various cancers Rudin et al. Its senolytic activity is explained by an overreliance of senescent cells on BCL-xL and BCL-w, both of which are up-regulated during senescence Yosef et al.

However, usage of navitoclax as a prophylactic senolytic drug is unlikely because of its severe thrombocytopenic and neutropenic effects Rudin et al. Recently, it has been shown that localization of p53 to the nucleus by FOXO4 protects against p53 engaging the pmitochondrial signaling axis and apoptosis therein Baar et al.

As with navitoclax, however, special attention must be paid to unintended effects of FOXO4 D-retro inverso isoform. For example, p21 CIP1 expression fell markedly in senescent cells treated with the peptide. Initial studies regarding senolytics are promising, but there are still lingering unknowns with regards to their effectivity as therapies.

Senescent cells were observed to reappear after cessation of senolytic treatment in a model of osteoarthritis Jeon et al. This could reflect unresolved damage from the anterior cruciate ligament injury surgery used in this study, although there is also the possibility that removal of senescent cells without targeting the causes that induce their accumulation could limit the benefits of senolytics.

Another potential problem of using senolytics is an acceleration of stem cell exhaustion. The clinical population in which senolytics could be used includes already-infirmed patients whose immune systems might be compromised. Can we expect an immune system that was unable to clear aberrantly accumulated senescent cells to infiltrate and clear apoptotic bodies? Without clearance of apoptotic bodies, secondary necrosis could result in the release of proinflammatory, danger-associated molecular patterns, further exacerbating systemic chronic inflammation.

This could limit the effective therapeutic window for senolytic drugs. Although these are potential caveats for senolytic therapies, they may be significantly outweighed by their benefits. With these unknowns, it will be critical to validate the kinetics of senescent cells clearance using robust markers of senescence and improved methods for identifying senescent cells Evangelou et al. Exploring alternative approaches to target the detrimental effects of senescence without resorting to senolytics may also be worthwhile.

One such approach would be targeting the SASP. Possible side effects of this strategy could include blunting the senescent response, exacerbation of the accumulation of senescent cells, or immunosuppression.

However, there are many potential routes for the development of new SASP modulators, which can be helped in no small part by improvements our understanding of how the SASP is regulated.

In summary, the past few years have unveiled a key role for senescence in aging. The advent of powerful genetic and pharmacological tools to dissect this relation should improve our understanding of the mechanisms through which the accumulation of senescence cells leads to age-related physiological decline. It should also inform in the development of new therapeutic approaches. Moreover, if targeting senescence using senolytics or by other strategies such as SASP-modulating drugs succeeds, it could not only contribute to the treatment of specific diseases but also improve the general health span of aged individuals.

The figures were designed using elements from Smart Servier medical art that are licensed under creative commons BY 3. The tive, the cell damage can be repaired. Otherwise, changes associated with old age can be divided when some of the repair mechanisms fail, damaged into a few categories: normal aging, somatic dis- DNA will accumulate, obstructing cellular function eases and multiple chronic conditions, psychologi- and causing its senescence.

Inducers of senescence, cal, cognitive and social changes Normal ag- such as telomere shortening, toxic agents or onco- ing implies sensory changes visual acuity, hearing genes, cause the formation of SAHF, that contain loss, dizziness , muscles weakening and reduced heterochromatin-forming proteins, such as hetero- mobility ability, fat changes.

All these cel- betes, osteoarthritis, osteoporosis, cancer, and lular characteristics can be considered as hallmarks several neurological disorders. In elderly there are or possible biomarkers of senescence. The phagocytic teins, vitamins C and E 51, In addition, there is function is reduced, while, chemotaxis may be a decreased number of functional glomeruli, de- conserved, especially in the presence stimulants of creased rate of glomerular filtration and renal the complement fragment C5a The number blood flow Occurrence of electrolytic distur- of macrophage precursors is decreased, the bances e.

The senile age is characterized by a high tary-adrenal systems. All these changes ing and senescence. Impaired NK function of natural killers NK is associated with Unlike acute transient inflammation in which the an occurrence of infective, atherosclerotic and causative agents are removed and the damaged neurodegenerative diseases. As the thymus exhib- tissue is cured, chronic inflammation persists for a its degenerative changes, impaired function of long time. During chronic inflammation affected both, B cells and T cells leads to imbalance be- tissues are infiltrated with macrophages and lym- tween inflammatory and anti-inflammatory mech- phocytes.

In addition, fibrous and necrosis of the anisms. Frequent infectious diseases in old age are affected tissue may occur 18, Chronic inflam- a result of impaired function of the innate and ac- mation is associated with many age-related physi- quired immune system. Immune system fails to ologic or pathophysiologic processes and diseas- clear infectious antigens, infected cells, senescent es. In normal, healthy aging, serum concentrations cells, and malignant transformed cells 56, At the same time, production of auto-antibodies responsible for the in elderly people concentration of anti-inflamma- occurrence of autoimmune diseases In the case of healthy aging, a balance be- age.

Still, there is no universally accepted defini- tween the action of pro-inflammatory and anti-in- tion of a biomarker of aging. Phenotypic hallmarks flammatory mediators has been established. Their are non-invasive biomarkers, and easy to obtain imbalance leads to aging of the body and to the Table 2. Biochemical biomarkers can reflect some development of various age-related pathological of the biochemical mechanisms underlying age conditions Senescence and aging Table 1. NO - nitric oxide.

NK — natural killer cells. NKT — natural killer T cell. Treg — T-regulatory cells. TCR — T-cell receptor. IL — interleukine. TLR — toll-like receptor. MHC — major histocompatibility complex. CD — cluster of differentiation.

FOXP - transcription factor protein. CCR — chemokine receptor. Adapted according to references In laboratory medicine, organ-specific bio- es, pathogenic processes or pharmacological re- markers imply determining those biochemical and sponses to therapeutic intervention 68, Thus, haematological analytes that point to the diseases there are diagnostic, prognostic, predictive and of particular organic systems.

Senescence and aging testing According to the American Federation for Aging Research AFAR recommendations, aging bio- In order to examine why and how people become markers should meet several criteria. They have to: old with different rate, it is necessary to define the 1. In mans and animals However, currently, there is this sense, the scientific community is continually no biomarker that would meet all of these criteria. Senescence and aging Table 2.

IGF-1 — insulin-like growth factor 1, somatomedin C. Erc — erythrocytes. B — blood. S — serum. P — plasma. ALT — alanine aminotransferase. AST — aspartate aminotransferase. GGT — gamma-glutamyl transferase. LH — luteinizing hormone. FSH — follicle-stimulating hormone. DHEA — dehydroepiandrosterone. Htc — haematocrit. Hb — haemoglobin. MCV — mean cell volume. Rtc — reticulocytes. I — increased. D — decreased. HD — increased in elderly hypertensive patients treated for their conditions.

Adapted according to reference Different methods for detec- Research on why and how the senescence goes on tion of senescence in tissue sections or in cultured should shed more light on this intriguing process. Senescence and aging Table 3. SAHF — senescence-associated heterochromatin foci.

PCR — polymerase chain reaction. FISH — fluorescent in situ hybridization. Telomere attrition is the in- southern blot analyses of the terminal restriction trinsic property of healthy cellular aging, and is fragments, by quantitative polymerase chain reac- also associated with many age-related diseases, tion or quantitative fluorescence in situ hybridiza- like atherosclerosis, myocardial infarction, heart tion It may be detected in tissue in consecutive sections; it means that multiple sections histochemically and immunohistochemi- possible biomarkers are not determined within cally 12, Although it was confirmed in to distinguish between different cell types that mouse tissues that most possible markers increase can be a source of senescent cells within complex with age, there is still insufficient data that would tissues, limiting our understanding of the underly- refer to healthy human tissues Telomere ing biological phenomena.

It has may be combined with additional possible bio- been a subject of debate whether telomere length markers, e. Senescence and aging sues and organs of the human body is not the the hallmarks and biomarkers of senescence and same 3, Therefore, In human aging, telomere aging. The knowledge of the mechanisms of se- length is a weak biomarker with poor predictive nescence and the influence of senescence on ag- accuracy.

Glycans might be a better possible bio- ing of organism have evolved due to the develop- marker of chronological and biological age than ment of numerous standard and sophisticated telomere lengths 81, Histochemical staining of and laboratory methods.

Senescence and aging lipofuscin i. Recently a new method cell cultures and animal leukocytes and intestinal for the determination of lipofuscin in liquid sam- crypt enterocytes, dermal fibroblasts, hepato- ples of stressed or damaged cells was introduced cytes, osteocytes, computational biology meth- Also, among potential predictors 5,7,10,11,16,17,,27,43,50,78,81,88,89 , etc.

In or- of biological age could be included the degree of der to successfully investigate these processes, it is methylation of DNA, transcriptomic predictors, necessary to find standardized biomarkers of se- proteomic predictors, metabolomics-based pre- nescence or the healthy aging of the organism dictors, and composite biomarker predictors It is important to know the extent of deter- Additional research is needed to confirm that gly- mining a particular biomarker to prevent age-re- cans or some other compounds will meet neces- lated assessment of the entire organism.

Standard- sary criteria to be the biomarkers of senescence. In ized biomarkers could also help in the monitoring the future, biomarker and therapeutic target can- of therapeutic interventions in the process of se- didates will be examined for a follow-up study, nescence, which is one of the goals of examining which will facilitate longitudinal monitoring of all aspects of senescence 11, Computational biology both the normal aging process and pathologies of aging refers to a wide range of data, from de- associated with aging.

Biomarkers genes in the control of rRNA gene transcription described in literature do not meet all criteria of In this review, 90 articles have been selected healthy aging. Addi- plex web of senescence and aging processes, tionally, a combination of multiple biomarkers but it will also open some new questions.

References 1. Strehler BL, ed. Understanding aging. In: Barnett YA, Bar- 9. Mrschtik M, Ryan KM. Lysosomal proteins in cell death nett CR, eds. Aging Methods and Protocols. Methods in Mo- and autophagy. FEBS J. Totowa: Humana Press Inc; Cellular se- 2.

Dyussenbayev A. The periods of human life. Glob J Hu- nescence in aging and age-related disease: from mecha- man-Social Sci. Nat Med.

Front Physiol. Cancer Sci. McHugh D, Gil J. Senescence and aging: Causes, consequ- Techniques to induce and quan- ences, and therapeutic avenues.

J Cell Biol. J Vis Exp. Cellular senescen- mir E, et al. Senescence, apoptosis or autophagy? When a ce and its effector programs. Genes Dev. Velarde MC, Menon R. Positive and negative effects of cel- 6. Senescen- lular senescence during female reproductive aging and ce in the aging process. J Endocrinol. Integrating cel- Nakazato M.

The impacts of cellular senescence in elderly lular senescence with the concept of damage accumulation pneumonia and in age-related lung diseases that increase in aging: Relevance for clearance of senescent cells. Aging the risk of respiratory infections. Int J Mol Sci. The role of senescent cells in aging.

The senescen- ; Cellular senescence controls fibrosis in wo- suppression. Annu Rev Pathol. Aging Albany NY. Senescence and aging Inflamma- heterogeneity in telomere-dependent senescence. PLoS Biol. Trends Mol Med. Unbiased analysis of senescence associated secre- Oxidative stress, aging, and diseases.

Clin following different genotoxic stresses. Interv Aging. Lujambio A. To clear, or not to clear senescent cells? That is Siderakis M, Tarsounas M, Telomere regulation and function the question.

Chromosome Res. Schmitt R. Senotherapy: growing old and staying young? Bernal A, Tusell L. Telomeres: Implications for cancer de- Pflugers Arch. Rafi MA, Alavi A. Debate on human aging and lifespan.

Bio- Telomere length in epidemiology: impacts. Mitochon- Epidemiol Rev. Telomere length in the newborn. Pedia- Senescence and apoptosis: dueling or complemen- tary cell fates?

EMBO Rep. Telomere length among the elderly and ol- Twin Res Hum Genet. EbioMe- combe M, Lu X et al. Telomere length and mortality: A stu- dicine. Am J Epidemiol. Cellular senescen- Barnes PJ. Mechanisms of development of morbidity in gitudinal study of semi-supercentenarians.

EbioMe- the elderly. Eur Respir J. Mitochondrial respira- Redox control of senescence and age-related disease. Biochem J. Redox Biology. ROS, cell senescence, and novel A novel sin- molecular mechanisms in aging and age-related diseases. Aging Cell. First line defence antioxidants- acel. Alexandria J Med. Glutathione and oxidative stress. Molecular dissection of for- chem Med Zagreb ; Oxidative stress, cellular senes- Mol Cell Biol. Markers of cellu- Telomere shortening as a marker of cellular et al.

Mitochondrial dysfunction accounts for the stochastic senescence. Aging ; A novel classification system for evolu- tion: effect on airway inflammation. J Allergy Clin Immunol. Front Genet. Theories of aging: An kland JL. A systems biology approach to the effect of ever-evolving field.