NAD is a cofactor of oxidation-reduction reactions and is a substrate for enzymes involved in cellular homeostasis. NAD levels decrease with aging and progeroid states, which is associated with metabolic abnormalities and fitness decline. The NAD-consuming enzymes such as CD38 and PARP1 have been shown to play a major role in this process. The accumulation of CD38+-inflammatory cells decreases NAD levels in aging. The small molecule 78c is a specific and potent inhibitor of CD38 that boosts NAD levels, improves survival of progeroid mice, and ameliorates several metabolic, structural, and molecular features of aging. However, to date the effect of CD38 inhibition on natural aging and longevity has not been explored. Here, we demonstrate that 78c increases the lifespan and healthspan of naturally aged male mice.

When offered the food to young mice ad libitum, 78c significantly boosted NAD, validating the 78c treatment. We then placed 1-year-old C57BL/6 male and female mice on either a control or 78c diet and closely followed their healthspan and longevity. When both sexes were grouped, treatment with 78c significantly improved longevity, with a maximal survival increase of 9%. When analyzing survival for males and females separately, a sex-specific effect of 78c was observed. The 78c-treated males had a 17% increase in median survival and a 14% increase in maximal lifespan compared with control. In females, no significant survival benefit was observed

We then evaluated the effect of 78c on the frailty in a cohort of old male mice. Frailty scores were derived from clinical examination. Changes in frailty index after 3 months were plotted in comparison with the baseline index. All animals in the control group had a significantly higher frailty index than that was 3 months earlier. By contrast, 78c showed a protection against age-related frailty increase.

In recent years, the function of the intestinal barrier has received increasing scientific attention as more and more intra- and extra-intestinal diseases, such as irritable bowel syndrome, inflammatory bowel diseases such as Crohn's disease, type 1 diabetes, colorectal cancer, acute inflammation-related diseases such as sepsis, and allergic diseases, were found to be associated with a dysfunctional intestinal barrier. The results of various animal studies demonstrated a link between intestinal barrier dysfunction and aging. For instance, aged monkeys had poorer intestinal barrier function, increased systemic inflammation, and higher microbial translocation compared to young animals. In Drosophila models, intestinal barrier dysfunction has been shown to predict the approaching death of flies.

In this review, we want to explore whether intestinal barrier dysfunction and the accompanying alterations to the intestinal microbiota composition are driving factors for the increasing proinflammatory status during aging known as inflammaging. Inflammaging was first described as a combination of a reduced ability to deal with stressors and the resulting increase in proinflammatory milieu. More recently, inflammaging was defined as a "chronic, sterile, low-grade inflammation" that occurs during aging. A similar concept is metaflammation, describing a metabolically driven inflammation caused by nutrient excess.

Due to the major role of the intestinal barrier in preventing bacterial toxins and pathogens from the intestinal lumen entering into circulation, an impaired barrier function or even minor changes in the regulation of the epithelial, microbial, biochemical, or immunological barrier might contribute to aging-associated decline as well as disease development.

The alterations found at the level of intestinal microbiota composition and intestinal barrier function in aging have been proposed to be interlinked with aging-associated decline in other organs, such as the liver. Due to its anatomical location receiving a more or less 'unfiltered' blood from the gut, the liver is confronted not only with nutrients, but also many xenobiotics, as well as bacterial toxins and metabolites stemming from the intestinal microbiota, along with endocrine mediators. This allows for a rather direct communication between the gut and the liver.

In summary, the gastrointestinal epithelial barrier, with its multiple layers and its various function, is affected by the physiological aging process. However, as its role in healthy aging or disease development becomes increasingly evident, attempts to restore the barrier function, e.g., through modulation via microbiota modifications, supplementing strains such as Lactobacillus plantarum or their metabolites, are of special interest. Besides microbiota modulation through probiotic strains or postbiotics, the current and future treatment of epithelial barrier dysfunction could include nutritional interventions and also bioactive pharmaceutical molecules, biologicals, or mucoprotectants.

Note that prior effective altruism discussions primarily focus on cryonics, although I prefer the term brain preservation because it is also compatible with non-cryogenic methods and anchors the discussion around the preservation quality of the brain. I'm not discussing whether individuals should sign themselves up for brain preservation, but rather whether it is a good use of altruistic resources to preserve people and perform research about brain preservation. It seems to me that:

(a) Most current technical arguments against brain preservation, to the extent that there are any at all, don't grapple with the possibility of structural inference. Because of the correlated nature of structural information in the brain, it is likely that there are numerous topological maps of the biomolecule-annotated connectome that could retain the information needed for long-term memories. Even if many of these maps were damaged or destroyed by aspects of the brain preservation procedure, if at least one could still be inferred, then the information content would still be present.

(b) Most extant arguments in the effective altruism community against brain preservation as a cause area don't grapple with QALY improvement/extension, and for unclear reasons treat humans as replaceable units, neglecting relational and psychological factors. If people think humans are replaceable, I think they should justify this, and also consider whether they are being consistent about it.

(c) With today's methods, brain preservation may already be among the best altruistic investments available from a QALY improvement/extension perspective, given reasonable estimates about the probability of success.

(d) With more research, substantially cheaper methods for structural brain preservation could potentially be developed, which could further improve the cost/benefit calculus. With more research, our uncertainty about different aspects of the brain preservation project could also be better clarified.

As a result of the above, and given its neglectedness, I think brain preservation for the prevention of involuntary death is one of the best areas for people interested in helping others to work in. I also think it is a great place for people who are interested in helping others to donate money. If you disagree, I would love to hear from you why that is. If you agree, I would love to discuss with you practical topics of how to best improve the field. Thanks for reading!

As scientists work toward finding a cure for Parkinson's disease, one line of research that has emerged focuses on mitochondria, the structures within cells that make energy. The health of those structures is maintained through a quality control system that balances two opposite processes: fission - one mitochondrion splitting in two - and fusion - two becoming one. When there's a problem with fission, that system is thrown out of balance. The consequences can include neurodegenerative diseases, such as Parkinson's disease, and other serious conditions.

A new study found that a protein in humans called CLUH acts to attract Drp1 to mitochondria and trigger fission. In experiments with fruit flies that were genetically engineered with an analog for Parkinson's disease, the team showed that damage from the disease could be reversed by increasing the amount of a protein that scientists call "clueless," which is the fruit fly equivalent of CLUH. "With a critically important pathway such as Drp1, there might be multiple proteins we could use to intervene and ultimately control Parkinson's disease. When we modified clueless in flies, symptoms analogous to Parkinson's disease improved substantially."

The team further showed that both clueless in flies and CLUH in human cells recruit free-floating Drp1 from within a cell to attach to receptors on the surface of mitochondria. In addition, the researchers discovered that CLUH in human cells helps translate the genetic instructions found in messenger RNA into the protein for Drp1 receptors on the surface of mitochondria. More available Drp1 receptors means that more Drp1 can be recruited in order to trigger fission.

Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation.

Importantly, drp1 overexpression rescues adult lethality, tissue disintegration, and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.

The longevity industry has now entered a new era, where various longevity technologies are being used by a growing cohort of subjects worldwide. As humanity enters this new era, subjects and their healthcare advisors, even employers such as military or insurance companies may require a classification system to assist in understanding what therapies should be implemented (or avoided) at what time during life. A simplistic classification system with five classes enables the public to easily see where they sit on a mortality scale and may provide motivation to change their lifestyle. This system is inversely proportional to mortality: the higher your class, the more probable you are to develop disease or undergo loss of life.

Type V - The Type 5 category perform rudimentary functions to maintain life, such as washing hands and using seatbelts in cars; however, their diet includes fast food and occasional healthy food, these subjects may hold excessive weight, and overall, they do very little to extend their life or health span. Mortality Risk - Probable.

Type IV - The Type 4 demographic exercise and eat relatively healthy and may use health supplements. Type 4's attempt to navigate away from toxins such as cigarettes, perform weight management, and may restrict or abstain from alcohol though do not implement any emerging or significant longevity technologies or regimes such as fasting or clean plant-based diets. Mortality Risk - Moderate.

Type III - The Type 3 class is proactive in using anti-aging technologies, they actively seek and study longevity for increased awareness, they use nicotinamide adenine dinucleotide precursors to maintain cellular metabolism and foods specifically known for their anti-aging properties, they possibly practice fasting, use fasting mimetics, exercise and are lean or muscular, target a more epigenetic diet, and steer clear of any biological insults. Mortality Risk - Unlikely.

Type II - The Type 2 cohort implement a strict longevity lifestyle that is very similar to Type 3's; however, Type 2's also implement early disease prevention strategies such as whole genome sequencing, whole exome sequencing, gene panel, single gene testing, and methylation analysis to garner data on their disease predisposition and penetrance. Other testing such as glycomic testing, blood plasma, and proteomic testing and other biomarkers that can assist in predicting and in some cases preventing disease are also used. Mortality Risk - Low.

Type I - Type 1's encompass everything that Type 2's perform; however, Type 1's have achieved a status of disease prevention and developed strategies to prevent further biological decay through various lifestyle decisions, including full spectrum diagnostic services, gene editing, and tissue reprogramming, and immune system or thymic rejuvenation to ensure high resistance to disease and dysfunction.

The scale shown here clearly demonstrates that there are various stages to longevity management that are completely distinguishable between one another. A classification system such as this also paves the way for governments to set goals and targets for their aging populations. Even though Type I status is not yet achievable, the scale intentionally includes this category, not only for future use, but as a symbol for humanity's scientific vision and quest to deliver a disease-free and much healthier society.

Previous experiments have shown that natural killer (NK) cells are partially responsible for the clearance of senescent cells from the human body. While some senescent cells have ways of avoiding detection and clearance, NK cells are attracted to certain parts of the senescence-associated secretory phenotype (SASP), which trigger them to kill the cells expressing it. Techniques are being developed to use this senolytic ability of NK cells as a potential therapy.

After taking NK cells out of whole blood, researchers sought to change the distribution of these cells. NK cells express different amounts of CD56 and CD16. NK cells that express high CD56 but low CD16 are immature and secrete interferon-γ; NK cells with low CD56 and high CD16 are responsible for cytotoxicity: the actual killing of other cells. The enrichment process, which involved activating the cells through the cytokine IL-2, substantially increased the percentages of both of these cell types.

These enriched cells were found to be very good at selectively eliminating senescent cells after 16 hours. In an experiment with one NK cell for every senescent cell, 15% of normal fibroblasts and 43% of senescent fibroblasts died. These numbers remained largely the same regardless of how senescence was induced, and endothelial cells yielded similar results to fibroblasts. Doubling or tripling the number of NK cells did kill more senescent cells; however, it also increased the number of normal cells being killed in the process. Therefore, instead of using more NK cells, the researchers increased the time in co-culture; while the number of normal fibroblasts dying remained low, only 10% of senescent cells survived after four days' exposure to fresh, enriched NK cells.

As we age, a biochemical pathway involving the signaling molecule PGD2 becomes more active, impairing immunity in two major ways: First, antigen-presenting cells called dendritic cells migrate less efficiently, slowing the adaptive T-cell and antibody responses. Second, white blood cells called neutrophils infiltrate infected tissues more aggressively, leading to damaging inflammation. Thus, the aged immune system is both slower to respond to new infections and more likely to overreact once it does mount a response. Bioage's drug BGE-175 inhibits this pathway by blocking the interaction between PGD2 and its receptor, a protein called DP1.

In the study, daily doses of BGE-175 protected aged mice from a lethal dose of SARS-CoV-2, the virus that causes COVID-19. Ninety percent of mice that received the drug survived, whereas all untreated control mice died. BGE-175 treatment was initiated two days after infection, when the mice were already ill, a time-frame relevant to real-life clinical situations in which patients would receive medication only after becoming symptomatic.

BGE-175 is currently in a Phase 2 clinical trial to test whether it can prevent disease progression and mortality in older patients hospitalized with COVID-19. "The promising preclinical data in this paper show that BGE-175 almost completely protects aged mice from lethality in a compelling model of human COVID-19. By reversing age-related declines in critical immune mechanisms, BGE-175 could allow older patients to more effectively fight off this disease."

Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria in muscle could trigger inflammation in the context of aging is still unknown.

Here, we demonstrate that BNIP3 plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of TLR9-dependent inflammation and activation of the NLRP3 inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans.

Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.

The association between inflammation and atherosclerosis is well established, and mechanistic studies have demonstrated that inflammation is an essential mediator of all stages of atherosclerosis, from initiation to progression and the development of thrombotic complications. Circulating immune cells play a critical role in the build-up of atherosclerotic plaques by adhering to activated endothelium and infiltrating the arterial wall to become lesional cells. This association has led to the study of various anti-inflammatory therapies in the last years.

The bone marrow (BM) is the primary site of haematopoiesis, and the proliferation and migration of haematopoietic progenitors are regulated by various physiological and pathological stimuli. Experimental studies suggest that increased BM haematopoietic activity may be a central link between cardiometabolic risk factors and exacerbated inflammation in atherosclerosis. In mice, hypercholesterolaemia and low HDL-cholesterol levels associated with elevated haematopoietic activity with increased monocytosis and neutrophilia. Hypertension, driven by an overactive sympathetic activation, deteriorates haematopoietic cell niche in the BM which can contribute to atherosclerosis. In humans, it has been suggested that chronic stress accelerates haematopoiesis, giving rise to higher levels of inflammatory cells that might contribute to the atherosclerotic process. In addition, haematopoietic stem cell division rates are increased in subjects with atherosclerosis, and it has been suggested that the haematopoietic system might be chronically affected in these subjects.

However, human data to support this association are sparse. Our purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis. Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals (median age 50.5) from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed. Systemic inflammation was indexed from circulating biomarkers.

Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis, i.e. plaque presence and burden.

Muscle fibre denervation and declining numbers of muscle stem (satellite) cells are defining characteristics of ageing skeletal muscle. The aim of this study was to investigate the potential for lifelong recreational exercise to offset muscle fibre denervation and compromised satellite cell content and function, both at rest and under challenged conditions. Sixteen elderly lifelong recreational exercisers (LLEX) were studied alongside groups of age-matched sedentary (SED) and young subjects. Lean body mass and maximal voluntary contraction were assessed, and a strength training bout was performed. From muscle biopsies, tissue and primary myogenic cell cultures were analysed by immunofluorescence and RT-qPCR to assess myofibre denervation and satellite cell quantity and function.

LLEX demonstrated superior muscle function under challenged conditions. When compared with SED, the muscle of LLEX was found to contain a greater content of satellite cells associated with type II myofibres specifically, along with higher mRNA levels of the beta and gamma acetylcholine receptors (AChR). No difference was observed between LLEX and SED for the proportion of denervated fibres or satellite cell function, as assessed in vitro by myogenic cell differentiation and fusion index assays. When compared with inactive counterparts, the skeletal muscle of lifelong exercisers is characterised by greater fatigue resistance under challenged conditions in vivo, together with a more youthful tissue satellite cell and AChR profile. Our data suggest a little recreational level exercise goes a long way in protecting against the emergence of classic phenotypic traits associated with the aged muscle.

A stem-cell theory of cancer predicates that not only does the cell affect the niche, the niche also affects the cell. It implicates that even though genetic makeup may be supreme, cellular context is key. When we attempt to solve the mystery of a long cancer-free life, perhaps we need to search no further than the genetics and epigenetics of the naked mole-rat. When we try to unlock the secrets in the longevity and quality of life, perhaps we need to look no further than the lifestyle and habits of the super centenarians. We speculate that people with Down's syndrome and progeria age faster but have fewer cancers, because they are depleted of stem cells, and, as a consequence, have fewer opportunities for stem cell defects that could predispose them to the development of cancer. We contemplate whether these incredible experiments of nature may provide irrefutable evidence that cancer is a stem-cell disease-fewer aberrant stem cells, fewer cancers; no defective stem cells, no cancer.

A stem-cell theory of aging and cancer reiterates a fundamental oncological principle: although genetic makeup may be pivotal, cellular context is paramount. When the genome and epigenome that regulate aging and malignancy are also stemness genes and stem-like properties, they reaffirm the key role that stem-cell quality and quantity play in longevity and cancer. We suspect that long-lived, cancer-spared mammals maintain a youthful genome and epigenome because they are equipped with a larger and healthier pool of stem cells. We contemplate that people with Down's syndrome and progeria age faster but have fewer cancers because they are depleted of stem cells and therefore have fewer opportunities for stem-cell defects that render one prone to cancer formation.

Therefore, the benefit of longevity needs to be balanced against the risk of malignancy. Intuitively, how we manage to conserve stemness and delay senescence is key.

Here, based on recent research evidence from our laboratory and others, we propose a mechanism - Senescence-Associated Cell Transition and Interaction (SACTAI) - to explain how cell heterogeneity arises during aging and how the interaction between somatic cells (SomCs) and senescent cells, some of which are derived from aging somatic cells, results in cell death and tissue degeneration. Recent genomic analysis reveals a remarkable heterogeneity of cell types during aging. Such cell heterogeneity gives rise to not only senescent cells but also other types of cells including progenitor and stromal cells.

Adult mesenchymal stem cells (MSCs) constitute a small percentage of cells responsible for repair upon tissue damage. The increase in senescent cells is tightly associated with repeated activation of adult MSCs, where they reach replication capacity and become senescent. In response to stress signals, differentiated SomCs may lose their identity and de-differentiate into MSC-like cells for repair. Such epigenetically re-programmed MSCs are subject to cell senescence triggered by replicative, mechanical, and inflammatory stress signals. Although in small numbers, senescent MSCs manifest the senescence-associated secretory phenotype (SASP), spread inflammation, and signal surrounding somatic cells in the tissue microenvironment. Thus, senescent MSCs may accumulate during aging by cell proliferation, transition, and senescence, and accelerate catabolism and death of somatic cells through cell interactions. Important signaling molecules mediating the SACTAI process include pro-inflammatory cytokine IL-1β, IL-6, IL-8, growth factor TGF-β, and morphogen Sonic Hedgehog, which at least partially overlap with SASPs.

SACTAI is a proposed two-step mechanism for aging-associated tissue degeneration and somatic cell death. In the first step, a few adult SomCs, in response to mechanical, inflammatory, or replicative stress signals, undergo proliferation, MSC transition, and senescence, resulting in senescent MSCs (snMSCs). This cell transition and senescence process results in a heterogenous cell population, which enables heterotypic cell interactions with each other. During the second step, snMSCs interacts with SomCs via SASPs. Such cell senescence-associated signaling contributes to cell death and tissue degeneration in age-related diseases. The newly discovered SomC transition to snMSC during aging may explain the fibrosis, abnormal ossification (calcification), and inflammaging phenotypes often associated with aging tissues. The identification of the multi-step mechanism of SACTAI provides an opportunity to develop potential drugs to intervene during different stages of age-related disease pathogenesis.

In 1961, researchers discovered that human fibroblast cells cultured in the laboratory could only divide a limited number of times, after which they stopped multiplying but remained metabolically active. This state was termed replicative senescence and was found to occur in a range of cell types. Further research revealed that senescence is caused by the shortening of caps, or 'telomeres', on the end of chromosomes. Every time a cell divides, its telomeres shrink until they reach a critical length that stops the cell from multiplying. New evidence showed that senescence is induced by cell stress as well as successive divisions, and that the number of senescent cells increases as tissues age.

Despite almost 60 years of research, many questions still remain about senescence; for instance, what happens to cells as they transition in to the senescent state? How does their metabolism change during this shift, and do they take on a new cell identity? Now researchers report the results of experiments that exquisitely profile the roadmap cells take on their path to senescence.

The team used a new experimental design to survey the entire genome and repertoire of RNAs, proteins, and metabolites present in fibroblasts cultured in the laboratory. These patterns were traced over time as the cells grew until they stopped dividing. The data revealed that RNAs known to be expressed in fully senescent cells progressively accumulate throughout the cell cycle. This suggests that senescent cells in vivo may be slowly amassing these features, but not yet expressing the classic biomarkers associated with the end-point of senescence, such as the beta-galactosidase enzyme.

The findings suggest that cells gradually acquire a number of changes on the path to replicative senescence: they express different genes, rewire their metabolic reactions and take on a new identity similar to mesenchymal cells. Previous studies have shown that removing senescent cells can increase the health- and life-span of mice. Therefore, interventions that target these early changes could help improve the well-being of individuals by stopping the cascade of events that lead to replicative senescence.

During aging, the liver undergoes a series of degenerative changes. Briefly, it presents a progressive decrease in functional liver mass, thus reducing its functional reserve, making it more difficult to maintain homeostasis and vulnerable to external stress or damage. Till now, the mechanisms underlying liver aging still remain unclear. As we known, the main causes of aging are DNA damage, telomere shortening, epigenetic alterations, and impairment of proteostasis.

The aged liver is usually accompanied with failure of regeneration, metabolic dysfunction, redox imbalance, and development of chronic or malignant liver diseases. The impairment of regenerative capacity in the aged liver is affected by both intracellular factors and extracellular factors. Intriguingly, we may be able to recover their regenerative capacity via changing a microenvironment for the senescent hepatocytes. The aging-related alterations in the liver form a unique microenvironment and affect a series of physiological processes. Moreover, this unique microenvironment may function as a vital role that causes the liver to become susceptible to chronic diseases or tumors. For instance, it affects the fate of hepatocytes and promotes neoplastic development. Moreover, hepatocytes in this microenvironment are more susceptible to ischemia/reperfusion (I/R) injury.

Of particular interest is the way to effectively eliminate the effects of aging and reverse the unique aging microenvironment in the aged liver. Modulation of autophagy could function as an effective strategy for reversing aging in the liver. Autophagy mainly functions as a cytoprotective role in liver diseases. Modulation of autophagy could markedly alleviate aging-related liver injury, promote liver regeneration, block I/R induced injury, and reverse the aging microenvironment in the aged liver.

Intervertebral disc degeneration (IVDD) refers to an age-related change that mainly occurs in the lumbar intervertebral disc and often precedes other age-related changes. During the process of IVDD, annulus fibrosis (AF), one of the important compositions of intervertebral disc, loses its original layer and toughness, and reticulated degeneration and hyalinization appear, while the percentage of water decreases in another component called nucleus pulposus (NP). As a result, the intervertebral disc loses its normal elasticity and tension.

Aging is the primary risk factor for the development of IVDD, which causes the accumulation of senescent cells in the intervertebral disc. Researchers have found that senescent NP cells play an important role in the initiation of IVDD. The number of senescent NP cells increased significantly during IVDD, suggesting the deleterious effect of senescent NP cells on the pathogenesis of IVDD. Recent studies have shown that senescent cells could secrete metabolic factors such as pro-inflammatory cytokines, matrix-degrading proteases, growth factors://en.wikipedia.org/wiki/Growth_factor">growth factors, and chemokines, which caused changes of the extracellular matrix (ECM). In addition, senescent cells can affect adjacent cells through paracrine signaling, thereby inducing the catabolism and inflammation in the microenvironment of intervertebral disc. The metabolic factors secreted by senescent cells are collectively named senescence-associated secretory phenotype (SASP).

In recent years, investigations on new drugs that target the process of senescence have become a new therapeutic strategy for the early prevention and latter treatment for degenerative diseases. Evidence suggest that whether through genetically modified strategy or chemotherapy, the elimination of p16INK4a senescent cells has been shown to significantly extend the healthspan in murine models. So, optimizing treatments to reduce senescence or eliminate senescent cells may exert positive effects on human health. Senolytic represents a wide range of drugs or small molecules that can selectively eliminate senescent cells. The application of senolytic drugs is a potential strategy for degenerative disease treatment, including IVDD.