What is the difference between senescence and aging

Abstracts, reports from meetings and case control studies were excluded. Articles published in English between and were included. Articles were selected according to relevance to the topic. It seems that the cellular response depends on the type of cell that is subjected to the harmful effect of the stressor.

While damaged lymphocytes tend to undergo apoptosis, damaged epithelial cells and fibroblasts tend to undergo senescence 5. The relationship between autophagy and apoptosis is complex. It is not yet clear which factor determines whether cells will die with apoptosis or with other mechanisms.

It seems that autophagy could be conducive to cell death in cases when apoptosis is inhibited 5. While activation of autophagy causes inhibition of apoptosis, its inhibition increases susceptibility to oxidative damage of the cell and apoptosis. Prolonged autophagy is associated with cell death. Autophagy becomes defective during ageing and especially in patients with age-related diseases, since degraded molecules and organelles accumulate in cells.

Hence, defective autophagy is a feature of old cells 7. Schematic depiction of the aging process, with possible therapeutic interventions is shown in Figure 1. Overview of the process of senescence and its contribution to aging of entire organism adapted according to references 5 , 10 and Based on kinetics of cell senescent processes there are two main categories of senescence — acute programmed, transient and chronic not programmed, persistent senescence.

While acute senescence leads to embryonic development, wound healing and tissue repair of specific populations of cells and tissues, chronic senescence that is not directed towards specific cells leads into a stable cell-cycle arrest, a state that limits the proliferation of damaged cells. The main mediator of acute senescence is SASP. It seems that, because of age-related immunodeficiency or less production of proinflammatory SASP factors, immune cells becomes inefficiently in the elimination of senescent cells.

Cancer development will occur if pre-senescent cells stressed cells would not been removed by specific mechanisms. However, it is not known which mechanisms are responsible for direction to senescence, apoptosis or to autophagy.

Early in life, senescent cells are transiently present and have a beneficial effect on development, homeostasis, and regeneration. However, at a later age, senescent cells accumulate and produce detrimental effects.

ROS — reactive oxygen species. SASP — senescence-associated secretory phenotype. Senescent cells are however functionally and metabolic active as changes occur, for example change of degradation pathways of proteins, enhanced mitochondrial metabolism, energy generation, etc. The purpose of senescent cells arrest is to limit the proliferation of damaged cells e. In young tissues, transient senescence has beneficial effect.

The good example is the beneficial effect of senescence to pregnancy that implies proper foetal development and time of parturition. A detrimental effect refers to reproductive capacity since it causes the decrease in the number of ovarian follicles, and in later age senescence causes decline in ovarian and uterine function Healthy senescence may be accelerated by elevating the concentration of oxygen or various toxic substances Factors that slow down damage accumulation delay the senescence.

Based on kinetics of cell senescent processes there are two main categories of senescence, i. Acute senescence is the part of normal biological processes, and has beneficial effect within tissues during embryonic development, wound healing or tissue repair.

Acute senescence may be a part of programmed mechanism of fibrosis control during tissue repair Acute senescent cells are eliminated through activation of senescence-associated secretory phenotype SASP factors and consequently activated immune clearance. Senescent cells, still metabolically active, found primarily in tissues with chronic inflammation and in renewable tissues, are able to create an inflammatory microenvironment, to recruit phagocytic cells for elimination of senescent cells and finally, to promote tissue removal.

They secrete a variety of different molecules to communicate with adjacent cells. Senescence is enabled with the acquisition of SASP factors, such as interleukins the most prominent is interleukin-6, IL-6 , chemokines, growth factors e. Released SASP factors are involved in sensitizing non-senescent neighbouring cells to senesce, cell proliferation, disruption of normal tissue structure and function, immunomodulation immune cells clearance , angiogenesis, disabling or fostering of cancer growth.

SASP factors have beneficial role during embryogenic development, accelerating wound healing, after tissue injury by limiting fibrosis , involved in the amplification and spread of senescent cells, during suppression of tumorigenesis by promoting the elimination of senescent cells.

The main function of SASP is to eliminate senescent cells. If there were no senescent cell clearance as in case in elderly people, senescent cells would accumulate, which would have detrimental consequences implying structural, degenerative, irreparable tissue damage and fibrosis 7 , Chronic senescence is induced through prolonged period of cellular stress or slow macromolecular damage 10 , Complex effector pathways involved in chronic senescence significantly differ from pathways in acute senescence, due to large SASP heterogeneity involved in chronic processes and high resistance of senescent cells to immune clearance.

Chronic senescence has detrimental effects within cells and tissues. The knowledge that senescence can cause age-related diseases has instigated researchers to develop drugs that can eliminate senescent cells.

These medications could improve health in the elderly Figure 1 11 , Senescent cells in elderly are not able to maintain neither physiological tissue functions nor tissue repair, including autophagy, whose capacity declines with aging 7 , 21 , Cellular senescence is followed by senescent cell clearance within those processes that are considered beneficial.

However, if the elimination of senescent cells does not occur, senescent cells accumulate and can lead to cancer and aging. Investigations on animal samples have shown that senescent cells accumulate in old animals in leukocytes and intestinal crypt enterocytes, in dermal fibroblasts, hepatocytes, osteocytes Unlike apoptosis in which phagocytes remove cells without causing inflammation, senescent cell survive because of stimulation of the inflammatory environment and removal of harmful compounds Its activity is present in lysosomes of senescent cells.

Senescence can be triggered e. Reactive oxygen species are a natural by-product of the normal oxygen metabolism. It is considered that ROS regulate several physiological functions, like signal transduction, gene expression and proliferation.

The major cellular sources of ROS are mitochondria, cell membranes and endoplasmic reticulum While lengthening of organismal lifespan is associated with low ROS concentration, senescent phenotype maintenance is endangered with high ROS concentrations Age-related accumulation of damaged macromolecules is one of mechanisms that contribute to the aging processes.

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

Pathways regulating senescence-mediated arrest. 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.

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.

Sign In or Create an Account. Advanced Search. User Tools. Sign In. Skip Nav Destination Article Navigation. Review November 07 Senescence and aging: Causes, consequences, and therapeutic avenues In Special Collection:. This Site. Google Scholar. Author and Article Information. Domhnall McHugh. Abbreviations used:. Received: August 14 Revision Received: October 09 Accepted: October 17 Online Issn: J Cell Biol 1 : 65— Article history Received:.

Revision Received:. Cite Icon Cite. The authors declare no competing financial interests. Search ADS. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Telomerase activation and rejuvenation of telomere length in stimulated T cells derived from serially transplanted hematopoietic stem cells.

Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Immune inflammation and disease progression in idiopathic pulmonary fibrosis. Portal chronic inflammation in nonalcoholic fatty liver disease NAFLD : a histologic marker of advanced NAFLD-Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Monitoring tumorigenesis and senescence in vivo with a p16 INK4a -luciferase model.

Association between telomere length in blood and mortality in people aged 60 years or older. Clearance of senescent cells by ABT rejuvenates aged hematopoietic stem cells in mice. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence.

Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. The senescence-associated secretory phenotype: the dark side of tumor suppression. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. Di Mitri. Robust, universal biomarker assay to detect senescent cells in biological specimens.

CCL5 secreted by senescent aged fibroblasts induces proliferation of prostate epithelial cells and expression of genes that modulate angiogenesis.

Chronic inflammation inflammaging and its potential contribution to age-associated diseases. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. NOTCH1 mediates a switch between two distinct secretomes during senescence.

Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.

Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment.

Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age.

Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Animal models of osteoarthritis: classification, update, and measurement of outcomes. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Idiopathic pulmonary fibrosis: immunohistochemical analysis provides fresh insights into lung tissue remodelling with implications for novel prognostic markers.

Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Liver fibrosis and repair: immune regulation of wound healing in a solid organ.

Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.

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Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Inflammation and frailty in the elderly: A systematic review and meta-analysis. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence.

Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Figure 1. View large Download slide. Figure 2. Figure 3. Figure 4. Volume , Issue 1. Previous Article Next Article.

View Metrics. Suggested Content Similarities and interplay between senescent cells and macrophages. HMGB2 holds the key to the senescence-associated secretory phenotype.

Email alerts Article Activity Alert. Complete Issue Alert. Daily Publication Alert. Close Modal. This site uses cookies. Overview and Key Difference 2. What is Aging 3. What is Senescence 4. Similarities Between Aging and Senescence 5. Aging is a gradual process by which a cell reaches senescence or cellular arrest.

The aging process takes place due to the accumulation of damaged DNA. These damages lead to the deterioration of the cells. Furthermore, during the aging process, cells undergo various aging promoting mechanisms such as lipid peroxidation, protein misfolding and mitochondrial damage. They will lead to the deterioration of the cell wall and other cellular contents of the cell. Prolonged accumulation of these events would cause the cells to reduce their functionality.

The accuracy of metabolic reactions will decrease. Moreover, the cells will utilize more amounts of energy to perform their functions. Due to these reasons, the cells will waste a high amount of energy at a faster rate, leading to the phenomenon of aging. Generally, the aging process takes place with time. But it can be induced by mutations occurring in the genome that affect the expression of proteins.

Therefore, aging can be made rapid by mutations. Moreover, different environmental exposures leading to epigenetics may also alter the rate of aging of a cell. Senescence is a result of aging.