Hematopoietic stem cell (HSC) aging is accompanied by hematopoietic reconstitution dysfunction, including loss of regenerative and engraftment ability, myeloid differentiation bias and elevated risks of hematopoietic malignancies. Gut microbiota, a key regulator of host health and immunity, has been recently reported to impact hematopoiesis. However, there is currently limited empirical evidence elucidating the direct impact of gut microbiome on aging hematopoiesis.

In this study, we performed fecal microbiota transplantation (FMT) from young mice to aged mice and observed significant increment in lymphoid differentiation and decrease in myeloid differentiation in aged recipient mice. Further, FMT from young mice rejuvenated aged HSCs with enhanced short-term and long-term hematopoietic repopulation capacity. Mechanistically, single-cell RNA sequencing deciphered that FMT from young mice mitigated inflammatory signals, upregulated FoxO signaling pathway and promoted lymphoid differentiation of HSCs during aging. Finally, integrated microbiome and metabolome analyses uncovered that FMT reshaped gut microbiota construction and metabolite landscape, and Lachnospiraceae and tryptophan-associated metabolites promoted the recovery of hematopoiesis and rejuvenated aged HSCs.

Together, our study highlights the paramount importance of the gut microbiota in HSC aging and provides insights into therapeutic strategies for aging-related hematologic disorders.

Cellular senescence, which is a normal consequence of aging, is characterized by irreversible cell cycle arrest in response to various stress stimuli, resistance to apoptosis and senescent-associated secretory phenotype (SASP). Cellular senescence is a cell fate decision and normal physiological event, which plays essential roles in development, prevention of cancer, and the wound healing process. However, when cells are subjected to sustained sub-lethal injury including radiation therapy or chemotherapy, continued oxidative stress and chronic inflammation prompt entry into cellular senescence. The chronic state of radiation-induced senescence together with secretion of pro-inflammatory factors, a phenomenon known as the SASP, contribute to the major pathology of radiation-induced normal tissue and organ injury.

Factors influencing the role of cellular senescence in the tumor tissue widely vary in part due to the tumor tissue heterogeneity, the oncogenic status, immune cell recognition by acute vs chronic senescence and radiation dose regimen, to name a few. For example, acute induction of cellular senescence is considered important for cancer prevention by stimulating the immune system to rapidly eliminate the genetically unstable cells, whereas chronic cellular senescence creates a tumor promoting environment through a secretion of SASP. Chronic cellular senescence also contribute to the radiation-induced late effects in the normal tissues and organs such as lung and skin fibrosis, cognitive dysfunction/necrosis to name a few. Overall, the SASP of senescent cancer cells is considered to be primarily detrimental in therapy resistance, immunosuppression and metastasis.

Senolytics are a class of drugs that selectively eliminate senescent cells. Multiple pharmacological strategies are under investigation to remove senescent cells. They include small molecules, peptides, and antibodies. Our new preliminary data show the potential of senolytic as well as anti-cancer agents to illustrate the foregoing point. Alvespimycin (17-DMAG), an HSP-90 inhibitor, reduced normal tissue damage after a radiation exposure without compromising radiotherapy effectiveness. Using another class of senolytics, other researchers have shown some functional and structural improvement in cardiovascular function, and radiation-induced muscle weakness using the combined senolytics, dasanitib and quercetin. Using another class of senolytics, navitoclax, a Bcl-2 family inhibitor, improved radiation-induced pulmonary fibrosis, radiation-induced hematotoxicity, age related hematopoietic stem cell (HSC) dysfunction, and delayed malignant glioma/en.wikipedia.org/wiki/Glioma">malignant glioma recurrence by eliminating the radiation-induced senescent astrocytes. The potential of navitoclax to mitigate normal tissue radiation damage while sensitizing radiation cytotoxicity in tumors is further supported by navitoclax's ability to overcome hypoxia-driven radiosensitivity.

The decline of autophagic ability is one of the most acknowledged molecular hallmarks of cellular aging. As eukaryotic organisms age, they suffer from a progressive, maladaptive decrease in the ability to activate autophagy and benefit from its degradative/renewal properties, leading the cells to accumulate damaged organelles and cytotoxic macromolecules overall. Autophagy appears to be intimately connected with the modulation of longevity, as proved by several studies which demonstrated an effect on cellular and organismal lifespan when autophagy was harnessed either genetically or pharmacologically. The exact mechanisms behind this connection are yet unclear, given the vastity of genes involved in the process and the different function afforded by autophagy including proteostasis, nutrient regulation, and immunity.

Evolution provides us with evidence of selective adaptations in the autophagic process across long-lived organisms, including phylogenetically close-to-humans taxa belonging to the mammalian clade. This confirms the existence of an either direct or indirect link between autophagy and lifespan modulation but concurrently may represent a unique opportunity to shed light on the key molecular elements involved through comparative studies. A connection between autophagic activity and organismal lifespan was first identified in a pioneering study on insulin/IGF-1 signalling, where autophagy-inducing mutations in daf-2 were associated with lifespan extension in C. elegans and later confirmed in organisms such as drosophila, mice, and humans. Another important discovery linking autophagy with longevity emerged from studies on mTOR signalling and dietary restriction, an established universal life-extending intervention. Starvation-induced autophagy was proven to be causal to lifespan extension in several animal models from yeasts to great apes.

Transcriptomic studies of the longest-lived mammal, the bowhead whale (Balaena mysticetus), revealed overexpression of genes for DNA repair, autophagy induction, and ubiquitination. To better inquire into the evolution of longevity in mammals, further studies were aimed towards the identification of unique adaptations in molecular markers of aging in taxa characterised by high longevity quotients. One of the most studied mammalian species characterised by a high longevity quotient is the naked mole rat (NMR, Heterocephalus glaber). This rodent is capable of living substantially more than expected more for a mammal of comparable body size. Interestingly, studies of the NMR showed higher basal autophagic activity (measured as expression of LC3II and beclin-1 autophagic marker proteins) when compared with C57Bl/6 mice. Furthermore, NMR's transcriptome analyses recapitulated features found in the bowhead whale, with overexpression of genes for DNA repair and autophagy, which proved down-regulated in mammals with low longevity quotients, such as mice and cattle.

A study on the speciation of another noncanonical rodent model characterized by a high longevity quotient, the blind mole rat (Spalax galili), revealed a strong dependence on proteostatic machineries such as autophagy and the proteasome in determining niche adaptation, since these animals need to deal with a high metabolic stress deriving from the limited nutrient sources of soil dwelling.

Another example of this phenomenon may be the case of the unique evolution witnessed in bats, the order of mammals with the highest longevity quotient among all. During the last years, several studies have been aimed to decipher the exceptional resistance of bats against aging and age-related diseases with many of these reporting an upregulation of autophagic activity across different tissues when compared with mice and other mammals. In a study on primary fibroblasts, both young and aged bats were found to have a constitutively higher level of autophagic flux than murine counterparts. Further analyses on the blood transcriptome showed upregulation of autophagy-associated genes and transcript enrichment for terms associated with macroautophagy and positive regulation of autophagy. Autophagy in bats arguably evolved to face the massive production of cytotoxic metabolic by-products deriving from the extremely energetically demanding activity of powered flight.

Finally, being aging now acknowledged as the driving cause of all age-related disorders, worth of interest are the evolutionary implications deriving from evidence of resistance from these diseases in the longest-lived mammalian models. Further attesting to autophagy as an anti-aging biological asset, recent studies found high autophagic activity to inversely correlate with the incidence and severity of pathologies associated with aging, such as neurodegeneration, frailty, and cancer. Bats are once again a unique study model as they show high cognitive performances (e.g., echolocation) throughout their extended lifespan, do not display phenotypic aging (young and old bats are macroscopically indistinguishable), and show lower occurrence of cancer when compared with other mammals.

Aging pathologies may be delayed, ameliorated, or prevented in aggregate by targeting the molecular foundations of the declines in homeostasis and function that arise over time. The knowledge of foundational targets suitable for such intervention remains limited, yet evolution has already leveraged such means, as is evident in the vast diversity of longevities in nature. Various species display aging-associated functional declines at wildly different rates and timings, including those that survive well beyond a human life span. As these traits are heritable and defining for many species, the underlying genetic mechanisms can be tracked through comparative genomic approaches.

There are many examples of long-lived animals. The Rougheye Rockfish, Sebastes aleutianus, is one such vertebrate species, with a maximum life span of over 205 years. Regardless of the aging mechanism - oxidative damage, proteostasis collapse, DNA damage, telomere/genomic maintenance, epigenetic drift, etc. - S. aleutianus resists the deleterious effects of age for over two centuries, enduring the variety of internal and external stressors assured with time. S. aleutianus is not the only rockfish lineage with this exceptional capability. The clade encompasses at least 107 extant species, ranging in maximum longevity from 11 to 205 years. Fortunately, multiple, independent lineages of rockfishes exhibit impressive life spans, imparting power into comparative approaches.

Our analyses reveal a common network of genes under convergent evolution, encompassing established aging regulators such as insulin signaling, yet also identify flavonoid (aryl-hydrocarbon) metabolism as a pathway modulating longevity. The selective pressures on these pathways indicate the ancestral state of rockfishes was long lived and that the changes in short-lived lineages are adaptive. These pathways were also used to explore genome-wide association studies of human longevity, identifying the aryl-hydrocarbon metabolism pathway to be significantly associated with human survival to the 99th percentile. This evolutionary intersection defines and cross-validates a previously unappreciated genetic architecture that associates with the evolution of longevity across vertebrates.

Recent developments in messenger RNA-modification techniques have enhanced the therapeutic efficiency of mRNA delivery and its potential for near-term clinical applications, including protein-replacement therapy and vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. However, the intrinsic inability and potential immunogenicity of mRNAs require that they be encapsulated within delivery vehicles. Current mRNA-delivery modalities centre on the usage of lipid nanoparticle (LNP) carriers for encapsulation and transport.

Extracellular vesicles (EVs), including exosomes and microvesicles, play a major role in the transport of biomolecules and nucleic acids, including mRNAs, within the human body. As a result, in recent years, EVs have emerged as promising carriers for nucleic-acid-based therapeutics owing to their intrinsic biocompatibility, their ability to cross physiological barriers and their low immunogenicity. Unlike LNPs, EVs, including exosomes, are endogenously produced by the body's cells and lead to lower levels of inflammatory responses. Moreover, strategies to cheaply and easily produce large quantities of exosomes have been developed.

We previously reported a cellular nanoporation (CNP) method in which transient nanometric pores were created on the surface of source cells to allow for the large-scale loading of full-transcript mRNAs into secreted EVs. Here, by using a mouse model of acute photoaging that closely mimics the pathophysiological features of aging-damaged skin in humans, we show the utility of exosome-based COL1A1 mRNA therapy to replace dermal collagen-protein loss as an anti-aging treatment for photoaged skin. To improve the efficiency of mRNA delivery and retention, we also show that the delivery of collagen mRNA via a hyaluronic acid (HA) microneedle (COL1A1-EV MN) patch allows for a more efficient distribution of mRNA in the dermis, resulting in durable collagen-protein engraftment and in an improved treatment of wrinkles in photoaged skin.

Aging results in an elevated burden of senescent cells, senescence-associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low-grade inflammation and a host of age-related diseases. Recent evidence suggests that the clearance of senescent cells alleviates chronic inflammation and its associated dysfunction and diseases. However, the effect of this intervention on metabolic function in old age remains poorly understood.

Here, we demonstrate that dasatinib and quercetin (D&Q) have senolytic effects, reducing age-related increase in senescence-associated β-galactosidase, expression of p16 and p21 gene and P16 protein in perigonadal white adipose tissue (pgWAT). This treatment also suppressed age-related increase in the expression of a subset of pro-inflammatory SASP genes (mcp1, tnf-α, il-1α, il-1β, il-6, cxcl2, and cxcl10), crown-like structures, abundance of T cells and macrophages in pgWAT. In the liver and skeletal muscle, we did not find a robust effect of D&Q on senescence and inflammatory SASP markers.

Although we did not observe an age-related difference in glucose tolerance, D&Q treatment improved fasting blood glucose and glucose tolerance in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin-stimulated suppression of plasma NEFAs, reduced fed and fasted plasma triglycerides, and improved systemic lipid tolerance. Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age. These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age.

The development of therapeutics to combat atherosclerotic cardiovascular disease (CVD) forms a significant part of humankind's battle against chronic disease. The basic pathological process of atherosclerosis has been characterized for over a century. Despite its multifaceted nature, the major clinical focus for treatment of atherosclerosis has involved targeting cholesterol metabolism to reduce the rate of plaque accumulation within blood vessels or improving recovery after a cardiovascular event. Of all therapeutic interventions, cholesterol-lowering statins dominate the CVD market. In fact, statins are the most commonly-prescribed drug in the world. In essence, the field of CVD therapeutics has adopted a strategy of slowing the rate of disease progression and reducing the risk of complications from disease (i.e. cardiovascular events, like heart attacks). Although this strategy has played a role in the significant increase in average human lifespan over the past century, it is essentially a disease management approach that has failed to erase CVD from the list of humanity's most prolific killers.

There are several downstream events that transform cholesterol into a toxic waste product. Most importantly, the development of atherosclerosis is contingent upon cholesterol penetrating blood vessels and becoming oxidized - making it non-degradable and toxic. This corrupted form of cholesterol ultimately drives an insidious cycle of low level chronic inflammation (inflammaging), macrophage dysfunction, and plaque accumulation. Cyclarity Therapeutics works to rehabilitate the cardiovascular system's own, natural self-repair mechanism, removing the toxic byproducts that cause macrophage dysfunction and restoring their natural ability to manage and reduce plaque. This is a "first in class" therapy that could redefine the treatment paradigm for atherosclerosis, paving a path for a new class of disease-modifying therapeutics. For the first time in the history of mankind's fight against chronic disease, the possibility of disease reversal has been enabled.

Cyclarity's candidate UDP-003 belongs to a class of compounds known as cyclodextrins. Cyclodextrins have special chemical properties that give them powerful fat/cholesterol binding capabilities. Cyclarity uses its novel computational platform technology to engineer cyclodextrins to enhance target specificity, safety, and efficacy relative to generic cyclodextrins. UDP-003 is designed to precisely bind and clear a toxic form of oxidized cholesterol, 7-ketocholesterol (7-KC), that builds up in immune cells (macrophages), transforming them into foam cells - the root cause of plaque formation.

Alzheimer's disease (AD) is the most prevalent form of dementia, affecting more than 50 million individuals worldwide. AD is a multifactorial disease with environmental (30%) and genetic (70%) causes. Environmental factors are usually associated with sporadic AD (SAD), while genetic factors are associated with familial AD (FAD) and SAD. Interestingly, FAD and SAD differ in age of onset. According to the age of onset, AD can be divided into two categories of early-onset AD (EOAD) and late-onset AD (LOAD) before or after the age of 65. In all AD cases, approximately 5% are EOAD and 95% are LOAD, indicating that most AD is caused by aging in concert with a complex interaction of genetic and environmental risk factors.

AD, especially LOAD, is associated with aging and is characterized by selective neuronal vulnerability (SNV). However, the relationship between aging and SNV and the molecular basis of AD are not completely understood which need to be urgently elucidated. Aging is the inevitable time-dependent decline in physiological organ integrity, leading to impaired function and increased vulnerability to death. It is characterized by nine tentative hallmarks grouped into three main categories: primary hallmarks (genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis), antagonistic hallmarks (deregulated nutrient sensing, altered mitochondrial function, and cellular senescence), and integrative hallmarks (stem cell exhaustion and altered intercellular communication).

To date, the role of each aging hallmark in AD development remains unclear. This article will focus on the primary aging hallmarks as these are interconnected with other aging characteristics and are at the base of the hierarchical order of aging features, and have been shown to be related to AD. It is an attempt to improve our understanding of the pathological mechanisms of AD to find potential therapeutic approaches and diagnostic tools.

Despite numerous interindividual differences, it is now clear that the composition of the microbiota of the elderly differs significantly from that of young and middle-aged people. Numerous progresses have been made on the study of the microbiota, and evidence is accumulating on the efficacy of therapies based on the microbiota, even if the clinical applications on obtaining the slowing down of aging are still lacking and more advanced human studies at strain-level resolution are required. The gut microbiota research should be pointed on specific signatures related to longevity. Future research should consider the individuals' baseline microbiome features and customize the therapies to meet their needs. Although knowledge on the microbiota in humans is limited, the present evidence led to hypothesizing strategies useful for maintaining a good state of health in the elderly.

A healthy lifestyle, with a balanced diet rich in unrefined foods of natural origin, together with adequate physical exercise, aerobic or combined, sustained for sufficiently long periods, allows for restoration and maintenance of a healthy microbiota even in old age, promoting healthy aging. Of course, prevention of the decline of the microbiota with a delayed onset of age-related pathologies should be preferred; however, a detailed knowledge of the actions of gut microorganisms will allow the formulation and diffusion of products containing supplements such as probiotics, prebiotics, and nutraceuticals with specific properties. Obviously, the use of supplements must be targeted, individualized and calibrated on the needs of the individual subject, and appropriate strategies must be implemented to maintain the restored microbiota.

In this review, we focalized on the influence of lifestyle on the maintenance of a healthy microbiota in the elderly and on the consequences on the general state of health of the subject. The effects of specific supplements were also highlighted, in order to suggest personalized microbiota-based strategies for healthy aging.

Mitochondrial dynamics regulate mitochondrial homeostasis through the modulation of multiple elements such as organelle interaction and mitochondrial morphology. In this study, we provide evidence that mitochondrial dynamics also controls the activation of intracellular inflammatory pathways. Our conclusion is based on a number of observations, namely that: a) repression of the mitochondrial fusion proteins Mfn1 or Mfn2 induces mitochondrial fragmentation and TLR9-dependent NFκB activation; and b) Drp1 or Fis1 repression causes mitochondrial elongation and both NFκB-dependent and type I IFN inflammatory responses.

Given the role of mitochondrial dynamics in regulating mitochondrial function and mitophagy, it is conceivable that alterations in these processes could be involved in triggering inflammation upon mitochondrial dynamics disturbances. Here, we show that indeed, the different manipulations induced by repressing Mfn1, Mfn2, Drp1, or Fis1 lead to very different patterns of alterations in mitochondrial membrane potential, mitochondrial superoxide production, mitochondrial mass, mitochondrial respiration, or mitophagy, which does not explain the inflammatory response observed in each condition. In contrast, we find that the inflammatory responses depend on the presence of mitochondrial DNA (mtDNA), which suggests that those changes in mitochondrial function and quality are consequences of adaptations in mitochondrial biology that are not directly related to the inflammatory response.

Mitochondrial stress can trigger sterile inflammation by inducing mtDNA mislocation and allowing mtDNA recognition by DNA sensors, mitochondrial dynamics are essential in maintaining mitochondrial homeostasis, and muscle inflammation and atrophy are hallmarks of impaired muscle health. Based on our findings, we propose that the maintenance of mitochondrial dynamics is a key factor in preventing the trigger of inflammatory responses characterized by mtDNA mislocation and DNA sensor activation, and that muscle inflammation induced by mitochondrial fragmentation plays a causative role in the development of muscle atrophy.

Cellular senescence and the senescence-associated secretory phenotype (SASP) are implicated in aging and age-related disease, and SASP-related inflammation is thought to contribute to tissue dysfunction in aging and diseased animals. However, whether and how SASP factors influence the regenerative capacity of tissues remains unclear. Here, using intestinal organoids as a model of tissue regeneration, we show that SASP factors released by senescent fibroblasts deregulate stem cell activity and differentiation and ultimately impair crypt formation.

The SASP (including factors like Ptk7, which are not technically secreted but are shed as a consequence of senescent cell surface remodeling) is believed to be a critical part of the contribution of senescent cells to age-related disease, primarily by influencing the tissue microenvironment and spreading senescence through a "bystander effect". Accordingly, selective elimination of senescent cells improves many aging symptoms and disease phenotypes. Our study identifies sPtk7 as a critical SASP factor that has a direct and reversible impact on intestinal stem cell proliferation and differentiation.

Our data show that Ptk7 is also expressed in fibroblasts and epithelial cells of the mouse small intestine, and that shedding of the N-terminal domain of Ptk7 is increased in the gut of old mice. Our co-culture experiments of intestinal organoids with senescent intestinal fibroblasts further show that fibroblast-derived Ptk7 impairs differentiation of intestinal stem cells. How this effect on intestinal stem cells influences epithelial homeostasis and regeneration remains to be established.

Type 2 diabetes is partly characterized by decreased β-cell mass and function which have been linked to cellular senescence. Despite a low basal proliferative rate of adult β-cells, they can respond to growth stimuli, but this proliferative capacity decreases with age and correlates with increased expression of senescence effector, p16Ink4a. We hypothesized that selective deletion of p16Ink4a-positive cells would enhance the proliferative capacity of the remaining β-cells due to the elimination of the local senescence-associated secretory phenotype (SASP).

We aimed to investigate the effects of p16Ink4a-positive cell removal on the mass and proliferative capacity of remaining β-cells using INK-ATTAC mice as a transgenic model of senolysis. Clearance of p16Ink4a positive subpopulation was tested in mice of different ages, males and females, and with two different insulin resistance models: high-fat diet (HFD) and insulin receptor antagonist (S961).

Clearance of p16Ink4a-positive cells did not affect the overall β-cell mass. β-cell proliferative capacity negatively correlated with cellular senescence load and clearance of p16Ink4a positive cells in 1-year-old HFD mice improved β-cell function and increased proliferative capacity in a subset of animals. Single-cell sequencing revealed that the targeted p16Ink4a subpopulation of β-cells is non-proliferative and non-SASP producing whereas the additional senescent subpopulations present in tissue remained contributing to continued local SASP secretion. In conclusion, deletion of p16Ink4a cells did not negatively impact beta-cell mass and blood glucose under basal and HFD conditions and proliferation was restored in a subset of HFD mice opening further therapeutic targets in the treatment of diabetes.

Researchers have recently leveraged the evolving proteomic approaches and single-cell RNA-sequencing technologies to begin to decode the functional impact of intertissue communication on brain aging. The application of molecular approaches to investigate systemic and lifestyle interventions, such as heterochronic parabiosis (in which the circulatory systems of young and aged animals are surgically connected), young blood plasma administration, exercise, and caloric restriction, has uncovered broad rejuvenating effects on the aged brain that are mediated through blood, which question the very notion that brain aging is immutable.

To what extent do pro-aging and pro-youthful factors act through convergent or divergent mechanisms? With respect to a common tissue of origin, the hematopoietic system and inflammatory processes emerge as a source of pro-aging factors. Nevertheless, in many cases, the cell type or tissue sources remain obfuscated. Although earlier work identified a series of muscle-derived myokines, the liver as a major secretory organ is rapidly emerging as an additional source of exercise-induced factors, with IGF1, GPLD1, SEPP1, and clusterin all being putative liver-derived exerkines.

Regarding mechanisms of action, numerous aging and rejuvenating factors exert similar effects on the brain; therefore, it is important to understand whether each factor acts through the same or parallel cellular targets and molecular pathways. Given the predominant immune nature of pro-aging factors in old blood, microglia appear an obvious first target. However, several recent studies are highlighting brain endothelial cells as a potential nexus by which pro-aging factors, including VCAM1, ASM, CyPA, and CCL2, regulate brain aging. Conversely, pro-youthful factors identified across interventions, such as GDF11, clusterin, GPLD1, and α-klotho, may likewise exert their rejuvenating effects indirectly on the aged brain by restoring function to the aging vasculature and additional peripheral targets.

Additionally, a series of pro-youthful factors, including TIMP2, osteocalcin, SPARCL1, and THSB4, appear to selectively enhance synaptic or cognitive functions; whereas others, such as FGF17 and SEPP1, have been demonstrated to regulate regenerative and stem cell functions. Collectively, these findings indicate that brain function can be restored through several parallel targets as well as direct and indirect mechanisms with relevance for future therapeutic approaches.

Osteopontin (OPN) is a multifunctional noncollagenous matrix phosphoprotein that is expressed both intracellularly and extracellularly in various tissues. As a growth regulatory protein and proinflammatory immunochemokine, OPN is involved in the pathological processes of many diseases. Recent studies have found that OPN is widely involved in the aging processes of multiple organs and tissues, such as T-cell senescence, atherosclerosis, skeletal muscle regeneration, osteoporosis, neurodegenerative changes, hematopoietic stem cell reconstruction, and retinal aging. However, the regulatory roles and mechanisms of OPN in the aging process of different tissues are not uniform, and OPN even has diverse roles in different developmental stages of the same tissue, generating uncertainty for the future study and utilization of OPN.

Numerous research results have shown the dual roles of OPN in the aging process. For example, in the nervous system, OPN not only causes neurotoxicity but also acts as a neuroprotective agent for Parkinson's disease. In the process of liver aging, OPN not only induces the occurrence and development of age-related liver fibrosis but also delays the aging and apoptosis of hepatocytes and promotes their regeneration by restoring the autophagy activity of aging liver cells. In addition, OPN also plays a dual role in the process of eye aging. On the one hand, in the early stage of the disease, OPN expression increases to mediate its protective effect on adverse pathological changes. On the other hand, excessive accumulation of OPN aggravates calcification and calcium deposition in tissues, which is an important link in pathological degeneration.

The role of OPN in the aging process has not been fully clarified. More importantly, the critical point of this phenomenon is not completely clear. Therefore, further in-depth studies investigating whether OPN mediates and participates in the effects of antiaging factors such as sports, nutrition, and healthy lifestyle on the aging process are worthwhile and will hopefully provide new ideas and treatment schemes for many clinical diseases in the future.

Skeletal muscle has a remarkable capacity to regenerate by activation of myogenic progenitor cells; however, both the number of these progenitors and their regenerative capacity decline with aging and cellular senescence. Metabolic changes such as impaired glycolysis, insulin sensitivity, and mitochondrial respiration are affected by senescence contributing to loss of the myoblast capacity to differentiate. Aging is also associated with impaired autophagy, which is essential to maintain satellite cell stemness and mitochondrial turn over.

Several studies found that the small molecule 2,6-disubstituted purine, reversine, increased cellular plasticity as demonstrated by increased differentiation potential of progenitor cells toward the neuroectodermal lineage; dedifferentiation of C2C12 myoblasts to a progenitor-like state; as well as dedifferentiation of sheep fibroblasts into multipotent progenitor cells, possibly via expression of the pluripotent factor, Oct4. Other studies reported that reversine may have anticancer properties. Indeed, reversine is an Aurora B protein kinase inhibitor, causing failure in mitotic chromosome segregation, cytokinesis, and cell proliferation.

Based on these results, we hypothesized that reversine might ameliorate the hallmarks of cellular senescence in human myoblasts. We discovered that short-term treatment of fully senescent myoblasts with reversine could restore insulin resistance, enhance glucose metabolism and oxidative phosphorylation, likely via reactivation of autophagy, ultimately restoring the differentiation ability of myoblasts to form myofibers. Our results suggest that reversine may have the potential to be used as a novel, antiaging treatment.