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.
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.
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. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network.
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Rodier, F. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Chen, H. MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype.
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Sperka, T. DNA damage checkpoints in stem cells, ageing and cancer. Inomata, K. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation.
This study demonstrates that DNA damage can induce stem cell differentiation. Wang, J. A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell , Schiroli, G. Precise gene editing preserves hematopoietic stem cell function following transient pmediated DNA damage response.
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Lujambio, A. The balance between oxidant generation and antioxidant processes in healthy tissues is maintained with a predominance of various antioxidants 30 , Reactive oxygen species of endogenous or exogenous origin induce and firm the senescent phenotype by a process that involves the response to DNA damage, epigenetic regulation and tumour suppression pathway activation e. As mitochondria are the main place of ROS creation, investigations have shown that mitochondrial dysfunction is associated with senescence, and consequently with the aging process.
It is considered that mtROS and oxidative stress in general can stimulate telomeres shortening and dysfunction, which is one of the characteristics of aging In addition to ROS, as senescence inducers, other mitochondrial-related effectors are also considered, for example, redox changes, changed metabolism 34 , The length of telomeres is an accurate predictor of the replicative ability of cells.
The basic function of telomeres is to protect the chromosomes from degradation rearrangements, end-to-end fusions, and chromosome loss Shortening occurs at each cellular division but is counteracted by telomerase.
Telomerase is an enzyme complex that maintains telomere length. It is considered that telomeres participate in the protection of ends of chromosomes from constitutive exposure to the DNA damage response Telomere length progressively shortens with replication of nuclear DNA during mitosis, or with oxidative stress or with senescence and aging While the length of the telomere at birth is about 11 to 15 kb in elderly it is significantly shorter, about 4 kb 39 - So, senescence is mostly triggered when the length of the telomere shorten from 5—20 kb to 4—7 kb The shortening of the telomeres that occurs during normal aging is controlled by the activity of specialized enzyme telomerase However, the balance between telomere shortening and counteracting by telomerase is disrupted during accelerated senescence as a result of the disease.
The DDR arrests cell cycle progression until damages are repaired. Mitochondria are intracellular source of oxygen. Functional mitochondria regulates cellular homeostasis through the maintenance of redox balance, which implies a balance between oxygen uptake, ATP production, membrane potential and generation of ROS Mitochondria that accumulate in senescent cells show increased concentrations of ROS and increased rate of senescent cells in the same tissues, resulting in mitochondrial dysfunction 27 , Today, several suppressors and cell cycle inhibitors are known, e.
Activation is triggered by the DNA damage, which may be result of telomeric and non-telomeric DNA damage or oxidative stress Senescent cells are characterised by flattened and enlarged morphology. They exhibit several molecular markers, including telomere-dysfunction-induced foci, senescence-associated heterochromatin foci SAHF , lipofuscin granules, DNA scars, altered gene expression 5 , 7. Another important feature of senescent cells is release of SASP factors These cells have special biochemical characteristics, e.
Nuclear and mitochondrial DNA damage accelerate senescence. As long as the repair mechanisms are effective, the cell damage can be repaired. Otherwise, when some of the repair mechanisms fail, damaged DNA will accumulate, obstructing cellular function and causing its senescence. All these cellular characteristics can be considered as hallmarks or possible biomarkers of senescence. Aging has been the focus of researchers for many years.
Consequently, there are a large number of aging theories that are classified in a variety of ways. For example, one of classifications theories includes the evolutionary and causality theories Evolutionary aging theories, that are focused on the failure of natural selection to affect late-life traits, refer to programmed aging assisted death , non-programmed aging and senemorphic aging maladaptive aging, secondary aging. Causality theories imply the influence of the environmental conditions on cellular senescence and ultimate death.
The main role was given to telomeres shortening, free radicals damages, spontaneous errors, glycation end-products There are also theories that attempt to explain the aging process itself - on the one hand there are theories considering the senescence as programmed processes; other theories, e. Aging is an intrinsic feature of all living beings. The complex process of biological aging is the result of genetic and, to a greater extent, environmental factors and time.
It occurs heterogeneously across multiple cells and tissues. As the rate of aging is not the same in all humans, the biological age does not have to be in accordance with the chronological age.
Many age-associated changes and hallmarks are evident in the human body. The changes associated with old age can be divided into a few categories: normal aging, somatic diseases and multiple chronic conditions, psychological, cognitive and social changes Normal aging implies sensory changes visual acuity, hearing loss, dizziness , muscles weakening and reduced mobility ability, fat changes.
At the same time the body increasingly succumbs to some diseases, including hypertension, cardiovascular diseases, diabetes, osteoarthritis, osteoporosis, cancer, and several neurological disorders.
In addition, there is a decreased number of functional glomeruli, decreased rate of glomerular filtration and renal blood flow Occurrence of electrolytic disturbances e. Also, there is a decrease in basal metabolism, the change in gastrointestinal system, as well as in the hypothalamic-pituitary-adrenal systems. The later results with low response to stimulation of this axis In the background of all the changes that occur during aging are three key factors — inflammation, immune aging and senescence.
Unlike acute transient inflammation in which the causative agents are removed and the damaged tissue is cured, chronic inflammation persists for a long time. During chronic inflammation affected tissues are infiltrated with macrophages and lymphocytes. In addition, fibrous and necrosis of the affected tissue may occur 18 , Chronic inflammation is associated with many age-related physiologic or pathophysiologic processes and diseases.
The role of anti-inflammatory cytokines is to neutralize pro-inflammatory cytokine activity, reduce chronic inflammation, and thus act protectively on tissues. In the case of healthy aging, a balance between the action of pro-inflammatory and anti-inflammatory mediators has been established.
Their imbalance leads to aging of the body and to the development of various age-related pathological conditions The weakening of unspecific innate and highly specific acquired immunity takes place through the aging of human cells Table 1. The phagocytic function is reduced, while, chemotaxis may be conserved, especially in the presence stimulants of the complement fragment C5a All these changes are responsible for the appearance of inflammatory and autoimmune diseases Impaired NK function of natural killers NK is associated with an occurrence of infective, atherosclerotic and neurodegenerative diseases.
As the thymus exhibits degenerative changes, impaired function of both, B cells and T cells leads to imbalance between inflammatory and anti-inflammatory mechanisms. Frequent infectious diseases in old age are a result of impaired function of the innate and acquired immune system. Immune system fails to clear infectious antigens, infected cells, senescent cells, and malignant transformed cells 56 , Immunological changes in elderly, based on the decline of the functional capacity of the immune system, result in reduced resistance to infections, increased appearance of neoplasia, and increased production of auto-antibodies responsible for the occurrence of autoimmune diseases As individuals of the same age do not have the same rate of age, there is a need to find specific hallmarks that could objectively determine the rate of age of a person.
Still, there is no universally accepted definition of a biomarker of aging. Phenotypic hallmarks are non-invasive biomarkers, and easy to obtain Table 2. Biochemical biomarkers can reflect some of the biochemical mechanisms underlying age status. It would be ideal if quantitative aging biomarkers could specifically determine the biological age healthy aging of a person, regardless of the predisposition to disease accelerated aging In laboratory medicine, organ-specific biomarkers imply determining those biochemical and haematological analytes that point to the diseases of particular organic systems.
Only in this way it will be possible to distinguish the phenomenon of aging due to the processes caused by various diseases that are commonly associated with the aging process. In this sense, the scientific community is continually investing great efforts in discovering such biomarkers. In general, a biomarker is defined as any substance, structure or process that can be objectively measured in the body or its products and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to therapeutic intervention 68 , Thus, there are diagnostic, prognostic, predictive and pharmacodynamic biomarkers.
They have to: 1. However, currently, there is no biomarker that would meet all of these criteria. Scientific papers refer at biomarkers of senescence or senescent cells as well as at aging biomarkers. Currently, due to the stated fact that many of the hallmarks do not meet biomarker definition criteria, it may be better to use terms a hallmarks of senescent cells or hallmarks of aging or b possible biomarkers of senescence.
Research on why and how the senescence goes on should shed more light on this intriguing process. The corresponding biomarker can be identified either in pro-senescent mechanisms either in anti-senescent pathways.
Different methods for detection of senescence in tissue sections or in cultured cells fibroblasts are used Table 3. It may be detected in tissue sections histochemically and immunohistochemically 12 , For more than a decade telomere length has most often average leukocyte telomere length been postulated as a biomarker of human aging These possible biomarkers are detected separately in consecutive sections; it means that multiple possible biomarkers are not determined within the same cells.
Although it was confirmed in mouse tissues that most possible markers increase with age, there is still insufficient data that would refer to healthy human tissues Telomere length measurement is emerging as a tool that may have implications for prevention, disease monitoring, and intervention development.
It has been a subject of debate whether telomere length is a biomarker of aging in specific tissues or for a whole organism, since the aging of different tissues and organs of the human body is not the same 3 , Therefore, In human aging, telomere length is a weak biomarker with poor predictive accuracy. Glycans might be a better possible biomarker of chronological and biological age than telomere lengths 81 , Histochemical staining of lipofuscin i. Recently a new method for the determination of lipofuscin in liquid samples of stressed or damaged cells was introduced Also, among potential predictors of biological age could be included the degree of methylation of DNA, transcriptomic predictors, proteomic predictors, metabolomics-based predictors, and composite biomarker predictors Additional research is needed to confirm that glycans or some other compounds will meet necessary criteria to be the biomarkers of senescence.
In the future, biomarker and therapeutic target candidates will be examined for a follow-up study, which will facilitate longitudinal monitoring of therapeutic interventions on senescence and aging. Today, the bioinformatics, as an interdisciplinary field of science, helps to analyse and interpret biological data on aging and senescence, including studies of gene expression and comparative and pathway analyses 88 - Computational biology of aging refers to a wide range of data, from demographic to genomic transcriptomic, proteomic and metabolomic studies CSGene database has been developed for exploring cell senescence genes and to highlight the roles of cell senescence genes in the control of rRNA gene transcription Between and , PubMed published about , articles on senescence and aging, and in the first four months of , more than 10, articles.
In this review, 90 articles have been selected to help us better understand the need to discover the hallmarks and biomarkers of senescence and aging.
The knowledge of the mechanisms of senescence and the influence of senescence on aging of organism have evolved due to the development of numerous standard and sophisticated and laboratory methods. Senescence and aging can be observed from different aspects so that this topic can be observed in the context of research of mainly human fibroblasts, leukocytes, cell cultures and animal leukocytes and intestinal crypt enterocytes, dermal fibroblasts, hepatocytes, osteocytes, computational biology methods, the examination of factors involved in the normal pathways of acute and chronic senescence, diseases that can affect the process of senescence, processes that can repair senescence effects 5 , 7 , 10 , 11 , 16 , 17 , 21 - 23 , 27 , 43 , 50 , 78 , 81 , 88 , 89 , etc.
In order to successfully investigate these processes, it is necessary to find standardized biomarkers of senescence or the healthy aging of the organism It is important to know the extent of determining a particular biomarker to prevent age-related assessment of the entire organism.
Standardized biomarkers could also help in the monitoring of therapeutic interventions in the process of senescence, which is one of the goals of examining all aspects of senescence 11 , The largest number of study of senescence and aging processes were made on cell cultures and animal models. The senescence seems to be a critical factor in both the normal aging process and pathologies associated with aging. Biomarkers described in literature do not meet all criteria of an ideal aging biomarker and actually represent various hallmarks of the aging process.
Most biomarkers currently being examined as senescence or aging biomarkers are related to age-related illnesses rather than the process of healthy aging. As the effector mechanisms of senescence are neither necessarily specific to senescence nor present in all forms of senescence the rate of senescence is not the same for all types of cells , the interpretation of existing biomarkers of senescence for now the hallmarks or possible biomarkers should be context dependent.
Additionally, a combination of multiple biomarkers should be used. Detection of biomarkers, in particular their quantification and validation, are necessary for understanding the senescence processes diagnostic biomarkers , monitoring of the rate of senescence prognostic and predictive biomarkers and the possible use of appropriate therapy intervention pharmacodynamic biomarkers. The identification and selection of reliable biomarker s , and the use of reproducible methods could help to better understanding of complex web of senescence and aging processes, but it will also open some new questions.
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