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: Rejuvenation therapies| Introduction | The crucial microenvironmental cues that cause differentiation abnormalities in MSCs are caused by hormonal, immunologic, and metabolic variables. For example, BMSCs in ageing could misdirect the differentiation toward adipocytes to impair osteogenesis, leading to the pathogenesis of osteoporosis. As the three-dimensional macromolecular network without cells, the ECM is primarily made of an interconnected system of fibrillar and non-fibrillar collagens, elastic fibers, and glycosaminoglycan-containing non-collagenous glycoproteins hyaluronan and proteoglycans. Certain enzymes that stimulate ECM destruction, like matrix metalloproteinases MMPs , mediate the ECM remodeling process. Many ECM genes and remodelers can be directly regulated by the mTOR signaling pathway, SIRTs, and numerous longevity-promoting transcription factors, such as KLF4, MYC, and HIF1, which control ECM dynamics during ageing. The ECM is necessary for normal tissue repair, but excessive deposition can cause organ malfunction and the onset of fibrotic and degenerative diseases. Especially, the adult dermis quality following complete maturation gradually deteriorates with age, such as atrophy of the elastic network, disintegration of collagen fibers, and alterations modifying proteoglycans. For instance, osteoarthritis OA might occur due to the altered matrix component composition, declining water content in the tissue, and increased catabolism in the ECM. Intercellular communication networks are essential for the coordination of biological processes in healthy and pathological settings of multicellular organisms. Senescence and ageing are influenced by interferences with intercellular communication caused by metabolic, mechanical, or biochemical triggers. To sustain physiologic function and respond to diseases, the many cell types that form the neurovascular unit NVU are in constant contact. The insufficient crosstalk between NVU cells impairs neurovascular coupling and blood-brain barrier dysfunction, thus leading to ageing and related neurological and neurovascular diseases. These communications form an intricate network involving various movements of metabolites between cellular compartments. The process of stem cell ageing and tissue and organ functional declining is attributed to mitochondrial-ER crosstalk. Senescent cells are extremely proactive and interact with nearby cells through a variety of intercellular channels, including SASP. As the traditional soluble SASP, soluble factors, growth factors, and matrix remodeling enzymes are released. Intercellular communication during senescence via receptor or cell-ECM interaction is referred to as nonclassical SASP, and emerging SASP components include EVs. EVs have negative impacts on downstream effectors at the levels of immunology, inflammation, gene expression, and metabolism in the ageing setting and age-related illnesses. Alterations in the systemic environment of cells and tissues play a role in the reversible process of ageing. Organ dysfunction with ageing is caused by blood-mediated cell-extrinsic alterations and important molecular mechanisms in the systemic environment. One of the cell types that reacts to young blood exposure is the hematopoietic stem cells HSCs. Many agonists and antagonists of specific signaling pathways have the effective capability of resetting tissue stem cells in aged organs into rejuvenating state. Heterochronic parabiosis is the surgical method of young and aged organisms using a common vascular system, showing the significant impact of the systemic environment on ageing and rejuvenation. However, the systemic and hormonal changes with age, including pro-inflammatory cytokine profiles and sex steroid changes, also influence stem cell transplantation effectiveness. The major types of stem cells include adult stem cells, embryonic stem cells ESCs , and iPSCs created by activating Yamanaka factors from various somatic cells. They have the unique capacity for self-renew and multipotency, and can differentiate into tissue-specific terminal cell types. MSCs are pluripotent cells developed from adult stem cells. Many studies have demonstrated that MSCs produced from various sources, such as bone marrow, adipose tissue, and umbilical cord blood, and MSC-derived compounds slowed ageing process and improved age-related conditions. Tissue stem cells play key roles in facilitating organic tissue renewal and performing regenerative responses to injury. iPSCs transform patient-specific samples from early cells into developed target tissues, showing potential for age reversal within the organism. With increasing age, decreased stem cell functionality can lead to diminished organ function and prolonged tissue repair. Targeting the age-related molecular basis of stem cells might reduce the deleterious effects of ageing. There are many rejuvenating approaches based on aged stem cells, such as delayed fasting, gene expression modulation, medicinal intervention, and niche changes. found that some rejuvenating approaches had no observable renewed effects on aged HSCs and aged bone marrow niches. Endothelial cells ECs and smooth muscle cells SMCs are critical building blocks of blood channels and are negatively impacted by premature or typical ageing processes. In ageing process, dysfunctional ECs and endothelial progenitor cells EPCs occur abnormal metabolism, the development into mesenchymal phenotype, vascular detachment, and myofibroblast formation, resulting in fibrosis and organ dysfunction. Dysfunction of pericytes, astrocytes, and endothelial cells increases blood-brain barrier permeability during ageing. EPCs might be obtained from the bloodstream or niches within the vascular wall and restored by the ectopic production of mediators that prevent senescence and the onset of ageing-related traits. The major stromal cell type is the fibroblast, which regulates tissue morphology by depositing ECM, and promotes cellular and microenvironmental homeostasis by secreting soluble substances and signaling proteins. During the ageing process, fibroblasts lose contractility and exhibit an unbalanced production and degradation of ECM proteins, ultimately leading to reduced connective tissue stiffness and even age-related diseases. Senescent cells SCs comprise a heterogeneous cell population because of their various cell-autonomous activation pathways and microenvironmental circumstances. Although cell-cycle arrested, SCs are still metabolically active and can perform various functions of the parent cells. High quantities of SCs secreting chronically SASP are found in aged tissues, causing irreversible reprogramming of their adjacent cells. Partial reprogramming of SCs can reduce the persistent inflammatory state related to ageing and secondary senescence in surrounding cells by inducing the SASP. During ageing, the immune system progressively undergoes disorders of immune cell generation, differentiation, and function, leading to a chronically subclinical inflammatory condition. Several studies have proposed that targeting central immunological processes and specific immune subpopulations can reduce specific age-induced immune changes. Macrophages reside in the bone marrow and are defective in efferocytosis and hyperactivated with ageing. Neutrophils can also function as an anti-inflammatory shift in macrophages by influencing the surrounding microenvironment or controlling the behavior of macrophages during tissue injury. The senescence in immune cells affects innate and adaptive immunity, particularly natural killer NK cells, B cell, and T cell function, potently driving age-related changes in solid organs. In vivo reprogramming might be significantly impeded by NK cells, which identify and eliminate partially converted cells in a degranulation-dependent mode. Some hormones, signaling pathways, cytokines, and growth factors might display T cell reconstitution effects and reduce the negative effects of age-related T cell deficiency. An in vitro B cell population with youthful characteristics and cellular reactivity to immunological stimulation can be revived after B cell depletion in elderly mice. Many specialized cells with different sources deserve further research for tissue and organ regeneration and rejuvenation. For example, in the vertebrate retinas, Müller cells serve as the primary supportive and protective glial cells. They can secrete various cytokines and exhibit the potential for self-renew and trans-differentiation into retinal neurons. Targeting β-cell and restoration of function is of vital importance for effective therapeutic strategies. For instance, the astrocytes and pancreas exocrine cells can be respectively direct reprogrammed into neuroblasts and β-cells via lineage-specific transcription factors. The known role of these signaling pathways is complex and mutually connected. Given the prominent association of signaling pathways with rejuvenation and ageing, targeting these signaling systems pharmacologically and therapeutically has great potential for rejuvenation and human health Fig. The target signaling pathways for cellular rejuvenation. Target signaling pathways for cellular rejuvenation are listed according to their biological functions. Many interventions, like dietary restriction and drugs, improve metabolism and extend longevity through nutrient-sensing pathways. In addition, targeting the pathways of damage-induced and developmental senescence can regulate the cell cycle and alleviate age-associated phenotypes. Modulating many inflammation pathways also provides an effective route to rejuvenation. Nutrient availability is crucial in regulating ageing and rejuvenation in mammals. Meanwhile, the AMPK pathway is a core mediator of energy homeostasis engaged in the pathobiology of ageing and age-linked disorders. The cell functionality can be hampered by persistent DNA damage, which can also accelerate senescence and apoptosis. Moreover, the alterations in the integrity and efficacy of mtDNA repair contribute to DNA damage accumulation, illness, and ageing. The cytosolic DNA sensor cyclic GMP-AMP Synthase cGAS binds to the effector protein stimulator of interferon genes STING , initiating a DNA sensing signaling pathway for innate immune responses. There are also a series of systems repairing the DNA, including BER, NER, and double-strand break DSB. Reactive oxygen species ROS are mainly generated from oxidative phosphorylation in mitochondria, and maintain a dynamic balance with antioxidation systems under physiological conditions. Low ROS levels enhance the defensive mechanisms by producing adaptive responses for stress tolerance and longevity, whereas high ROS levels create insufficient adaptive responses that may accelerate the onset and course of ageing. Besides, mtDNA is susceptible to damage by mitochondrial ROS. Peroxiredoxins have been shown to facilitate ROS-based redox signaling and to trigger many cellular stress responses. Metabolic stress, hypoxia, protein damage, and mitochondrial ROS all can impair mitochondrial protein homeostasis and functions. The transcriptional activation program of mitochondrial chaperone proteins and proteases is known as the mitochondrial unfolded protein response UPR mt , which is a mitochondrial response to stress. Activating transcription factor associated with stress-1 ATFS-1 participates in the upregulation of genes involved in multiple stress response pathways for organismal survival of acute stressors. Meanwhile, in the initial development stages of elderly individuals, age-dependent levels of histone 3 methylation partially influence UPR mt activation. However, prolonged UPR mt activation might also induce the propagation of mitochondrial damage. Multiple signaling cascades whose integration targets the induction of senescence, ageing, and associated disorders can be activated by the cycle of physiological interactions between inflammation and oxidative stress. In mammals, the major pro-inflammatory cytokines, which include interleukin-6 IL-6 , tumor necrosis factor-α TNF-α , and IL-1α, significantly remodel the immune system. The NF-κB signaling pathway is highly linked with the initiation and deterioration of tissue inflammation and ageing process. NF-κB can induce pro-inflammatory mediators, SASP, chemokines, and adhesion molecules, and the crosstalk between upstream signaling elements including MAPK, mTOR, and protein kinase B affects the transcriptional activity of NF-κB. Therefore, these shared pathways might provide a common route to rejuvenation by modulating inflammation, and some distinct pathways have great potential of targeting improving specific functions. The transforming growth factor beta TGF-β superfamily is a vast protein group, including three TGF-βs TGF-β1—3 , bone morphogenetic proteins BMPs , and growth differentiation factors GDFs. Many findings on age-related diseases have reported that TGF-β signaling dysfunction or increased levels of TGF-β ligands induce metabolic dysfunction, tissue fibrosis, inflammation, regeneration suppression, and cell degeneration. Meanwhile, ageing also induces many abnormalities at the TGF-β receptor level. TGF-β signaling possesses dual functionality and versatility in some age-related disorders and cancer as a suppressor and a promoter. TGF-β signaling can regulate matrix protein synthesis and matrix degradation, and alter cell-cell interaction. TGF-β overexpression results in ECM deposition, epithelial—mesenchymal transition EMT , and cancer-associated fibroblast CAF formation, then leading to fibrosis and cancer. For preservation and transition from the pluripotent state during embryo development, stem cells need β-catenin to moderate the response to Wnt signaling. Increased Wnt signaling has been found in aged organisms and excessive levels of Wnt are damaging to organism functionality. iPSC reprogramming is widely defined as the rejuvenation of mature differentiated cells to an embryonic-like fate. The transcriptome, epigenome, and metabolome of differentiated cells can be significantly altered by the transient expression of Yamanaka factors OCT4, SOX2, KLF4, and cMYC; OSKM , which can also remodel the cells into iPSCs. But in distinct subpopulations of fibroblasts, the change of fibroblast component and the level of secreted inflammatory cytokines might affect the in vitro reprogramming effectiveness and in vivo wound healing rate. The iPSC reprogramming technique has extensive potential for molecular regeneration, disease modeling, and drug discovery. The somatic cells of elderly donors can be utilized to generate human iPSCs, and cell reprogramming can reverse the key signs of ageing. By lengthening telomeres, reorganizing the mitochondrial network, alleviating oxidative stress, and recovering pluripotency, the reprogramming process transforms aged cells into young condition. Telomere malfunction and chromosomal fragility can impair the ability of iPSCs to self-renew and the developmental pluripotency to differentiate. Moreover, in the cells with telomere and mitochondria defects, somatic cell nuclear transfer SCNT -mediated reprogramming might be a better technology than current reprogramming factors. In addition, iPSCs can be reprogrammed from patient cells via small molecules, miRNAs, and combinations of reprogramming factors, and be differentiated into somatic cells for drug testing and regenerative medicine. However, many studies clarified that ageing also might constitute critical barriers to cell reprogramming due to cellular senescence, inflammation, telomere reduction, and metabolic alterations. The differentiated cells or premature termination of reprogramming can also carry the gene mutation and the full genetic heritage of the patient, which might contribute to long-term risk and tumor formation. Studies have proved that some longevity-promoting compounds and inhibition of age-related pathways enhance reprogramming in regenerative therapy. There are also many methods to boost the safety of iPSCs, such as using suicide genes to eradicate any undifferentiated iPSCs that remain after therapy, choosing younger donors, using appropriate cell sources, improving gene delivery techniques, replacing DNA delivery with proteins, mRNA, or regulatory miRNAs, using small-molecule DNA modifiers, and using low-passage iPSCs. Lineage reprogramming, also described as direct reprogramming, is the procedure of switching somatic cells from one lineage to another with no transition for intermediate pluripotent states. For instance, recent research demonstrated that certain pro-neural transcription factors can directly reprogram non-neural somatic cells into neurons, skipping the pluripotent stage. Meanwhile, because of the unique advantages of in situ conversion in live organs, lineage reprogramming is efficient and suitable for in vivo tissue repair and rejuvenation. Direct reprogramming in vivo may also benefit from minimizing hazards for genetic changes during prolonged in vitro culture, cancer development associated with de-differentiation, and immunological rejection following transplantation. The senescent program induced by ageing process and tissue damage can offer a beneficial microenvironment for in vivo lineage reprogramming. Chiche et al. suggested that tissue damage induced senescence and SASP secretion to promote the plasticity of resident cells, promoting in vivo reprogramming in tissue repair and regeneration. This technology can be built to utilize numerous and convenient autologous patient-derived cell types as a source, and is particularly crucial to replicate age-related traits and mimic the onset pathophysiology of diseases. Cell reprogramming is a stepwise protocol. Studies have proved that somatic cell reprogramming mediated by OSKM for fewer than 7 days induced transient cellular alterations and reversible dysplasia, but partial reprogramming induction for more than 7 days could lead to tumor formation. The cellular re-differentiation to the original phenotype with epigenome rejuvenation and the ability to react to optimum cocktails of certain differentiation factors is the representative feature of partial reprogramming. Generally, it is difficult to distinguish between the underlying epigenetic alterations that rejuvenate ageing cells and the changes that regulate the shift in cellular identity. Partial reprogramming is able to restore the common features of cellular ageing without altering the identity or function of the cells. Chondronasiou et al. demonstrated that partial and reversible reprogramming could improve the ageing states in cells, increase the ability of old mice to restore tissue damage, and lengthen the lifespan of progeroid mice. Epigenetic remodeling is associated with biochemical modifications to the genome, leading to an altered response of gene transcription to physiological stimuli. DNA methylation clocks might detect a wide range of ageing-related epigenetic modifications that are indicative of genomic, cell biological, and tissue changes that occur during life. Protein-protein interactions can induce allosteric regulatory sites in complicated epigenetic machinery. During reprogramming without de-differentiation, the mobility of heterochromatin protein 1β, an essential epigenetic modifier, has been proved to increase in SCs and promote epigenetic rejuvenation. For epigenetic rejuvenation, distinguishing the rejuvenative features of reprogramming from dedifferentiation is a strong development. Mitochondria role in epigenetic processes mostly involves alterations in DNA methylation, histone modification in nuclear chromatin, and posttranslational gene control by noncoding miRNAs. Differential mtDNA methylation is associated with various conditions, including ageing and ageing-related diseases, changed metabolism, alterations in circadian rhythm, and even cancer. Moreover, the conserved histone lysine demethylases JMJD Besides, all metabolic intermediates that serve as substrates or cofactors for epigenetic alterations originate from the Krebs cycle and other mitochondrial metabolic pathways. Alternate splicing, different promoter or enhancer usage, ncRNAs, and epigenetic changes that impact the structure and function of chromatin all can modulate transcription. Retrotransposon-mediated promoters might also promote gene regulation and expand protein diversity for phenotypic variation and embryo development. During ageing, heterochromatin decay might upregulate the level of silent retrotransposons, leading to promoted mobility of retro-transposable elements RTEs within genomes and cellular homeostasis disruption. In nascent RNAs of human cells, m 6 A actively regulates the expression level of both autonomous LINEs and co-transcribed LINE relics, facilitating the retrotransposition of LINE. The inflammatory response can trigger epigenetic alterations, and epigenetics in turn can interfere with inflammation action. In reaction to severe inflammatory events, transitory activation of NF-κB-related innate immunity and senescence-related inflammatory elements might enhance reparative cellular reprogramming. DNA methylation and histone acetylation are correlated with TNF-α expression during development and inflammatory disorders. For instance, Sera et al. found that the X-chromosome-specific enzyme, UTX, maintained the expression of downregulated genes during ageing via demethylase-dependent and -independent epigenetic modulation, contributing to hematopoietic homeostasis and inflammation regulation. Ageing is unavoidably accompanied by a diminished capacity to maintain tissue integrity and function. Cell or tissue rejuvenation without dedifferentiation is known as epigenetic rejuvenation, and it leads to a more youthful functional state and reversed ageing molecular markers. In addition, epigenetic modifications can target several druggable pathways. In addition, senotherapy can increase lifespan, restore the functionality of bone marrow, muscle, and skin progenitor cells, enhance vasomotor function, and decrease the onset of atherosclerosis. Mitochondria is responsible for the ATP production required for organisms and apoptosis, autophagy, the creation of iron-sulfur clusters, amino acid synthesis, copper and lipid metabolism. Conversely, the disturbed mitochondrial dynamics, like genetic ablation of mitochondrial fusion and fission components, also cause metabolic changes. Age-related disruption in energy balance and an increased propensity for age-related illnesses may be caused by the reduction in mitochondrial activity. The crosstalk between mitochondria and other organelles like lysosomes might also lead to increased oxidative stress, reduced ATP production, and breakdown of cellular catabolic mechanisms, ultimately inducing metabolic imbalance and ageing. The mitochondrial functions in energy homeostasis and metabolism are closely associated with protein quality control factors in disease and age-related disorders, such as PTEN-induced putative kinase 1 PINK1 , Parkin, and TNFR-associated protein 1 TRAP1. Mitochondria also segregate many critical metabolic pathways, like the TCA cycle, fatty acid β-oxidation, and the one-carbon cycle. The synthesis of mitochondrial metabolites in these pathways might be involved in additional mechanisms that control stem cell activity and fate decisions. The Mitophagy pathway functions as a crucial mitochondrial switching that guides bioenergetic transition and metabolome remodeling attributes, to eventually define the effectiveness and quality of nuclear reprogramming and stemness transition in somatic cells. Thus, mitochondrial targeting or mitophagy regulation can promote metabolic remodeling, playing potential roles in rejuvenation and regeneration. Deregulation of the redox state causes a rise of peroxides, ROS, and free radicals, which are collectively known as oxidative stress. Adaptive cellular responses to pathogenic challenges in ageing and age-associated disease tolerance, such as ischemia tolerance, can also be greatly benefited by moderate oxidative stress caused by diverse stressors. It has been demonstrated in numerous human cohorts and animal experiments that oxidative damage and inflammation might promote a state of susceptibility and raise the possibility of unfavorable health outcomes. For oxidative damage regulation, bioactive exosomes have antioxidant effects on reducing the excessive ROS, promoting intracellular anti-oxidative stress defense, immunomodulation by blocking excessive ROS and changing mitochondrial function. There are some promising antioxidant or anti-inflammatory substances, like minerals, vitamins, fatty acids, and antioxidant phytochemicals, to postpone skeletal muscle ageing and the onset of sarcopenia. Autophagy is a conserved, physiologic, and self-protective mechanism that supports cellular homeostasis and stress adaption. Autophagosomes with bilayered membrane vesicles can capture the degraded cellular components and subsequently merge with the lysosome to digest long-lived proteins, excess or damaged organelles, and misfolded or aggregation-prone proteins. Depending on the selective autophagic degradation of several organelles, autophagy is subdivided into mitophagy, aggrephagy, pexophagy, reticulophagy, nucleophagy, lysophagy, xenophagy, lipophagy, ferritinophagy, and glycophagy. Autophagy serves as one of the central pathways in the protection against functional loss and increased vulnerability to ageing process and age-related disorders. The activity of autophagy and the autophagy gene transcription by specific transcription factors, epigenetic changes, and microRNAs have emerged as crucially conserved pathways for promoting lifespan. Enhancing the function of the autophagy-lysosome system can eradicate age-related organelle degeneration, which might have regenerative benefits for cellular rejuvenation. The molecular circadian oscillator consists of transcriptional and translational feedback loops that are interlocked. BMAL1 and CLOCK or NPAS2 have the ability to heterodimerize and bind to E-box elements of many clock-controlled genes to drive transcription. As PER and CRY degrade over the night, negative regulation of BMAL1 and CLOCK is released, allowing the beginning of a new circadian day. In addition, the molecular clock controls the rhythmic expression of genes related to numerous cellular processes and nutrient-sensing pathways, which provides feedback to the primary clock system. Almost all the major genes implicated in the modulation of the circadian cycle have been found to induce alterations in circadian rhythms in their absence and to have an impact on health status. Thus, improving intracellular synchronization and the synchronization between SCN network and central and peripheral clocks might restore accuracy and stability to the ageing circadian system. Melatonin, produced in the pineal gland and mitochondria, participates in complicated intracellular signaling pathways with anti-ageing, antioxidant, chemopreventive, immunostimulatory, and tumor-inhibitory functions. Stem cells contain a functional circadian clock whose rhythmicity contributes to the multipotent cell properties in constant renewal and injury response. Multipotent stem cells from various organs also have distinct clock gene expression profiles with various amplitude ranges. Histone alterations, DNA modifications, non-coding RNAs, huge multisubunit chromatin remodeling complexes, and additional epigenetic changes are also significant points in the circadian modulation of stem cell destiny. With ageing, stem cells receive signals from endogenous and external factors operated through circadian rhythms and epigenetic clocks. The circadian output and oscillator system have adapted to the particular homeostatic requirements of the adult stem cell region in the young organism. But the circadian functions of ageing stem cells might switch toward a stress-dominated program. found that the overexpression of CLOCK could rejuvenate physiologically and pathologically aged human MSCs. Hence, circadian clock regulation provides opportunities to rejuvenate stem cells for various tissue engineering approaches. The oscillations of peripheral clocks in numerous peripheral tissues, including the heart, liver, adipose tissue, retina, and multiple brain regions, can be controlled by synchronizing the circadian clock produced by SCN neurons. Cell-autonomous circadian oscillations also have a substantial impact on the physiology and pathology of peripheral organs. Many studies have suggested that circadian rhythms might be in a noticeably different phase during development in one cell or tissue type compared to another part of the body. These alterations in tissue-specific clocks might affect immune hyperactivation with ageing. Besides, tissue susceptibility and reactions to toxicity also change during the circadian cycle, which indicates the development of drug timing administration. The molecular mechanisms that mediate cellular and organ ageing provide therapeutic targets for cellular rejuvenation. The increasingly rejuvenative approaches have been developed, and the schematic overview of strategies for cell rejuvenation is shown in Fig. It contains cellular reprogramming, clearance of SCs and SASP inhibitor, metabolic manipulation, the restoration of aged stem cell function, microenvironment remodeling, resetting the circadian clock, immune rejuvenation, and heterochronic parabiosis. Especially, cellular reprogramming can rejuvenate the terminally differentiated cells to the pluripotent state or epigenetically unstable intermediates, and also to another desired cell type for tissue repair. The reprogramming technology mainly includes iPSCs, partial reprogramming, and direct reprogramming Fig. Schematic overview of strategies for cell rejuvenation. Various strategies have been developed for cell rejuvenation that leverage intrinsic and extrinsic factors, including epigenetic reprogramming, genetic enhancement, autophagy modulation, and metabolic manipulation. Furthermore, small molecules, growth factors and cytokines, blood factors, iPSC technology, clearance of senescent cells and SASP, microenvironment regulation, and circadian clock modulation can also exert great influences on cell rejuvenation. iPSCs induced pluripotent stem cells, SASP senescence-associated secretory phenotype. Reprogramming approaches for rejuvenation. The iPSC-mediated cell reprogramming is a protocol that somatic cells are first dedifferentiated into iPSC and then differentiated into the desired somatic cells. Partial reprogramming refers to a short exposure to Yamanaka factors only generates intermediates with high plasticity. Transforming somatic cells from one lineage to another without transitioning through intermediary pluripotent stages is known as direct lineage reprogramming. The biological age of our cells, tissues, and organs is determined by an epigenetic clock based on alterations in the DNA methylation profile. A change in permission for future development and a return to a more flexible and pluripotent state are made possible by the removed DNA methylation instruction, and the production of iPSCs can also get around epigenetic constraints and change DNA methylation patterns to support youthful states in cells. These cells eventually adapted to closely resemble ESCs. iPSCs can be derived from different tissue-specific cell types, such as human endometrial cells, endothelial cells in the placental artery, amnion-derived cells, fibroblast, blood cells, and even cancer cells. Senescent and centenarian cells are revived through pluripotent reprogramming, and the iPSCs produced from these cells have reset telomere length, gene expression profiles, oxidative stress, and mitochondrial metabolism. Currently, given that each random integration event of a retrovirus poses a possible genetic risk, despite some of these approaches have produced lower efficiency than conventional reprogramming of retroviral administration, they constitute a step closer to therapeutic application. Using partial reprogramming, the epigenetic age of cells can be reduced without losing cell identity, suggesting that full reprogramming of iPSCs is not necessary to reverse ageing of somatic cells. In vitro cellular reprogramming has observed alleviation of age-associated phenotypes and the reset of age clock. Due to the physiological complexity of the ageing process, it is necessary to study in vivo reprogramming to gain a deeper understanding of how it can affect cellular and organismal ageing. Ocampo et al. reported that transient cyclic induction of OSKM in vivo ameliorated age-associated hallmarks, extended lifespan in progeroid mice, and promoted tissue repair from streptozotocin-induced pancreatic damage as well as cardiotoxin-caused muscle damage, with no resulting teratoma formation. For example, expression of OSKM specifically in hepatocytes can dedifferentiate adult hepatocytes into progenitor cells and promote cell proliferation concurrently, and functionally, short-term in vivo reprogramming increases liver plasticity and promotes regeneration. and the short-term OSKM expression reduces myocardial infarction-induced damage and improves cardiac function. In vivo reprogramming with short-term cyclic expression of OSKM also inhibits the progression of intervertebral disc degeneration IDD , and significantly improves senescence-associated phenotypes in ageing nucleus pulposus cells NPCs. The first is teratomas, a type of tumor that could be cancerous, which may be attributable to too much OSKM induced by inappropriate dosage. DNA methylation-targeted drugs mainly contain DNA methyltransferase inhibitors, like 5-Azacytidine. The removal of DNA methylation is a prerequisite for epigenetic rejuvenation and the generation of iPSCs. BETi has exhibited the effect to induce keratinocytes dedifferentiation, to enhance the migratory ability in keratinocytes in vitro, and to promote skin wound healing in vivo. The 3-deazaneplanocin A DZNep compound, which specifically inhibits H3K27me3 and H4K20me3, is crucial for activating OCT4 during iPSC reprogramming. HDAC inhibitors have the ability to reverse the deacetylation of histone tails and trigger the expression of specific genes. Recent advances in our understanding of gene manipulation against age and age-related diseases have prompted several distinct interventional strategies. The first one is the repression of senescence-associated genes to delay or reverse senescence. For example, identifying the driving role of the histone acetyltransferase gene KAT7 in senescence in the Werner syndrome WS and Hutchinson-Gilford progeria syndrome HGPS models via genome-wide CRISPR-Cas9-based screening. Analysis of proteomic and transcriptomic datasets revealed senescent cell antiapoptotic pathways SCAPs , covering Bcl-2 family members, ephrins, PI3K isoforms, p21CIP1, HIF-1α, and plasminogen-activated inhibitors 1 and 2 PAI-1 and -2 , were indeed more highly expressed in senescent than non-senescent cells, which is responsible for the resistance of SCs to apoptosis. Furthermore, the dominant SCAPs also vary with different cell types, which expands the limitations of genetic silence of SCAPs to remove SCs. Genetic strategy against senescence also can be achieved by overexpression of longevity gene to reset gene expression in SCs. Telomerase reverse transcriptase TERT and follistatin FST gene therapy using high-capacity cytomegalovirus vector by intranasal inhalation or injection significantly improved phenotypes associated with healthy ageing and extended lifespan in mice without severe side effects. Further, TERT reduced the telomere shortening associated with ageing, and both therapies halted the degeneration of the mitochondrial structure. gov in the world NCT Another study reported the gene therapy with three longevity genes FGF21, sTGF-βR2, and αKlotho treated multiple age-related diseases. The association between SCs burden and health span helps to discover chemicals that selectively remove senescent cells. The fact that SCs exhibit resistance to apoptosis supports the idea that these SCs rely on antiapoptotic, pro-survival mechanisms to prevent self-destruction. Based on bioinformatic analysis, forty-six compounds that target SCAP pathways have been identified as possibly senolytic. D has the ability to trigger apoptosis brought on by dependency receptors, like as ephrins, in part through blocking Src kinase. For example, senescent human pre-adipocytes or MSCs are susceptible to D but not Q or F, while senescent HUVECs are susceptible to Q or F but not D. Navitoclax ABT , a potent antagonist of BCL-2 and BCL-xL, eliminates senescent myocytes and hematopoietic stem cells but not senescent pre-adipocyte. albeit not senescent human pre-adipocytes. Despite the apoptotic SCs induced by senolytic strategies, such apoptotic cells are still finally removed by the immune system. NK cells, macrophages, and cytotoxic T cells are innate and adaptive immune cells that carry out immunosurveillance of SCs and play a crucial role in their elimination when they are young or under physiological conditions. The interaction between the activating NKG2D receptor and its ligands expressed on SCs determines the involvement of NK cells in the elimination of SCs. In cycling human endometrium, decidual senescence is required to support embryonic implantation, and acute decidual senescence can promote the release of IL and attract uterine NKs, further selectively targeting and clearing senescent decidual cells through the interaction of NKG2D and DNAM1 receptors-mediated granule exocytosis. After delivery, MOs are crucial in removing senescent uterine cells to preserve postpartum uterine activity, which helps to maintain the likelihood that a second pregnancy would be successful. Accumulating evidences have demonstrated that SCs could be cleared by immune cells, which could be a lever for lowering the burden of SCs. Suppressing the SASP also has been an alternative strategy for combating cellular senescence-associated phenotypes or diseases. p38MAPK is the MAPK family member and also an important regulator of the SASP, and p38MAPK inhibitors including SB, UR, and BIRB , potently suppressed SASP expression in SCs. Of note, unlike the intermittent administration of senolytic drugs, most SASP inhibitors are needed to maintain suppression of SASP in a manner of continuous treatment, which raises the likelihood of side effects compared to senolytics taken on an intermittent schedule. The metabolic disturbance is known to drive the function decline of adult stem cells with respect to ageing, and the mechanism by which nutrient-sensitive signaling pathways such as the mTOR and AMPK pathways play a central role. Long-term 1 year rapamycin treatment increased memory and learning in both young and old mice, but it also improved some of these traits in young animals, suggesting that rapamycin has beneficial effects that are age-independent. Metformin also contributes to metabolic-induced rejuvenation by regulating nutrient-sensitive signaling. elegans by activating AMPK in a LKB1-dependent mechanism. To maintain genomic integrity and tissue homeostasis, adult tissue-specific stem and progenitor cells have defensive mechanisms that reduce endogenous DNA damage. However, the DNA repair response in stem cells declines with ageing, which results in the loss of stem cell properties and DNA damage-caused cellular senescence and organ atrophy. In telomere-dysfunctional animals, administration of the NMN preserves telomere length, inhibits the DNA damage response and p53, enhances mitochondrial activity, and reverses liver fibrosis. The conducive effect of proteostasis loss on stem cell ageing inspires the strategy of protein homeostasis to protect stem cell function. Numerous chemical chaperones, including 4-Phenylbutyric Acid 4-PBA and its derivatives, have been shown to exhibit anti-amyloidogenic activity and to prevent misfolding protein aggregation. By increasing partially folded proteins and stabilizing their more compact native structures, 4-PBA can reduce the formation of unfolded aggregates and increase the pool of folding intermediates. It can also change the structure of Hsps to increase the exposure of hydrophobic surfaces, which improves Hsp chaperone activities. The depletion of adult stem cell pool with age contributes to tissue degeneration, so maintaining tissue homeostasis into old age requires replenishing the stem cell pools. Stem cell transplantation is a therapeutic intervention, and it has been extensively researched as a way for the replenishment of regenerative cells to provide stem cells from an unaffected donor or gene-corrected autologous cells to the recipient. A large number of adult stem cells are available for autograft or allograft therapy, but only HSCs transplantation is widely accepted and used clinically, which has been demonstrated to be successful in treating hematologic disorders such as leukemia and lymphoma. For example, EpSCs transplantation can regulate inflammation response, remodel the microenvironment of skin wounds, recapitulate tissue integrity and promote diabetic wound healing. More importantly, transplanted MuSCs also accessed the satellite cell compartment, replenishing the endogenous stem cell pool and taking part in injury repair. As research progressed, Zheng and his colleagues went on to publish more research exploring the CD42 signaling mechanism. Among them articles in Cell Stem Cell , Nature, Experimental Cell Research , Leukemia and Aging Cell. The potential applications of this technology are vast and could impact patients in several key areas:. With its ability to revolutionize blood and immune system recovery, amplify the effectiveness of therapeutic agents, increase transplantation success, and provide comprehensive therapy for individuals with compromised immune systems, this breakthrough has the potential to transform many areas of medical treatment. My lab focuses on studies of the physiological and pathological function and the mechanism of regulation of Rho family GTP-binding proteins. The Research Horizons blog features news and insights about the latest discoveries and innovations developed by the scientists of Cincinnati Children's. This blog does not provide medical advice, diagnosis, or treatment. Home Announcements Cancer Stem Cell Rejuvenation Technology Licensed to Mogling Bio. Stem Cell Rejuvenation Technology Licensed to Mogling Bio. Enhancing the effectiveness of therapeutic agents: The release of leukemia-initiating cells from the bone marrow increases their susceptibility to chemotherapeutic agents, potentially improving treatment outcomes for leukemia patients. Increasing the rate of transplantation success: By administering CASIN, there was effective opening of bone marrow niche, allowing for improved engraftment of the donor stem cells. Another group was treated from 12 through 22 months, approximately age 35 to 70 in humans. And a third group was treated for just one month at age 25 months, similar to age 80 in humans. Compared to control animals, there were no blood cell alterations or neurological changes in the mice that had received the Yamanaka factors. Moreover, the team found no cancers in any of the groups of animals. When the researchers looked at normal signs of aging in the animals that had undergone the treatment, they found that the mice, in many ways, resembled younger animals. In both the kidneys and skin, the epigenetics of treated animals more closely resembled epigenetic patterns seen in younger animals. When injured, the skin cells of treated animals had a greater ability to proliferate and were less likely to form permanent scars—older animals usually show less skin cell proliferation and more scarring. Moreover, metabolic molecules in the blood of treated animals did not show normal age-related changes. This youthfulness was observed in the animals treated for seven or 10 months with the Yamanaka factors, but not the animals treated for just one month. This suggests that the treatment is not simply pausing aging, but actively turning it backwards—although more research is needed to differentiate between the two. The team is now planning future research to analyze how specific molecules and genes are changed by long-term treatment with the Yamanaka factors. They are also developing new ways of delivering the factors. Belmonte is currently an Institute Director at Altos Labs, Inc. Other authors included Mako Yamamoto, Isabel Guillen Guillen, Sanjeeb Sahu, Chao Wang, Yosu Luque, Javier Prieto, Lei Shi, Kensaku Shojima, Tomoaki Hishida and Concepcion Rodriguez Esteban of Salk; Kristen Browder, Zijuan Lai, Qingling Li, Feroza Choudhury, Weng Wong, Yuxin Liang, Dewakar Sangaraju, Wendy Sandoval, Michal Pawlak, Jason Vander Heiden and Heinrich Jasper of Genentech, Inc. |
| Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases | The Research Horizons blog features news and insights about the latest discoveries and innovations developed by the scientists of Cincinnati Children's. This blog does not provide medical advice, diagnosis, or treatment. Home Announcements Cancer Stem Cell Rejuvenation Technology Licensed to Mogling Bio. Stem Cell Rejuvenation Technology Licensed to Mogling Bio. Enhancing the effectiveness of therapeutic agents: The release of leukemia-initiating cells from the bone marrow increases their susceptibility to chemotherapeutic agents, potentially improving treatment outcomes for leukemia patients. Increasing the rate of transplantation success: By administering CASIN, there was effective opening of bone marrow niche, allowing for improved engraftment of the donor stem cells. This suggests that this technology can enhance the success of transplantation procedures. Providing comprehensive therapy for immunocompromised patients: By optimizing HSC mobilization and engraftment, this technology holds promise as a holistic therapeutic approach for individuals with compromised immune systems. Research By. Yi Zheng, PhD. Previous Post. Next Post. Related Posts Potent Carcinogen Detected in Third-Hand Smoke Residue February 2, New Research Tool Seeks to Accelerate Hunt for Cancer Immunotherapy Targets January 17, Research Areas Asthma and Allergy Big Data and Analytics Cancer Community Health Diabetes and Obesity Digestive System Emergency and Critical Care Genomics and Development Heart and Lung Imaging Sciences Infectious Diseases and Vaccines Mental and Behavioral Health Organoids Ortho, Sports Med and Rehab Perinatal Population Health and Equity Quality and Safety Rare Diseases Research Annual Report Research Annual Report Research Annual Report Research Annual Report Research Foundation News Rheumatic Disorders Sensory Systems Surgical Science Tools for Science. Latest Posts. How Neuroimaging Illuminates Links Between CHD and Mental Health February 12, This suggests that the treatment is not simply pausing aging, but actively turning it backwards—although more research is needed to differentiate between the two. The team is now planning future research to analyze how specific molecules and genes are changed by long-term treatment with the Yamanaka factors. They are also developing new ways of delivering the factors. Belmonte is currently an Institute Director at Altos Labs, Inc. Other authors included Mako Yamamoto, Isabel Guillen Guillen, Sanjeeb Sahu, Chao Wang, Yosu Luque, Javier Prieto, Lei Shi, Kensaku Shojima, Tomoaki Hishida and Concepcion Rodriguez Esteban of Salk; Kristen Browder, Zijuan Lai, Qingling Li, Feroza Choudhury, Weng Wong, Yuxin Liang, Dewakar Sangaraju, Wendy Sandoval, Michal Pawlak, Jason Vander Heiden and Heinrich Jasper of Genentech, Inc. The study was supported by Universidad Católica San Antonio de Murcia UCAM , and Fundación Dr. Pedro Guillén. In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice. Kristen Browder, Pradeep Reddy, Mako Yamamoto, Amin Haghani, Isabel Guillen Guillen, Sanjeeb Sahu, Chao Wang, Yosu Luque, Javier Prieto, Lei Shi, Kensaku Shojima, Tomoaki Hishida, Zijuan Lai, Qingling Li, Feroza K. Choudhury, Weng R. Wong, Yuxin Liang, Dewakar Sangaraju, Wendy Sandoval, Concepcion Rodriguez Esteban, Estrella Nuñez Delicado, Pedro Guillen Garcia, Michal Pawlak, Jason A Vander Heiden, Steve Horvath, Heinrich Jasper, Juan Carlos Izpisua Belmonte. Office of Communications Tel: press salk. Unlocking the secrets of life itself is the driving force behind the Salk Institute. Our team of world-class, award-winning scientists pushes the boundaries of knowledge in areas such as neuroscience, cancer research, aging, immunobiology, plant biology, computational biology and more. Founded by Jonas Salk, developer of the first safe and effective polio vaccine, the Institute is an independent, nonprofit research organization and architectural landmark: small by choice, intimate by nature, and fearless in the face of any challenge. March 7, Cellular rejuvenation therapy safely reverses signs of aging in mice Salk researchers treated mice with anti-aging regimen beginning in middle age and found no increase in cancer or other health problems later on. Salk News. TITLE In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice. AUTHORS Kristen Browder, Pradeep Reddy, Mako Yamamoto, Amin Haghani, Isabel Guillen Guillen, Sanjeeb Sahu, Chao Wang, Yosu Luque, Javier Prieto, Lei Shi, Kensaku Shojima, Tomoaki Hishida, Zijuan Lai, Qingling Li, Feroza K. Research Areas Healthy Aging. For More Information Office of Communications Tel: press salk. The Salk Institute For Biological Studies: Unlocking the secrets of life itself is the driving force behind the Salk Institute. |
| Rejuvenation Therapy – An Overview | ANOVA IRM Germany | The post-mortal characters in the Revelation Space series have long-term or essentially infinite lifespans, and sheer boredom induces them to undertake activities of extreme risk. DNA methylation dynamics in aging: how far are we from understanding the mechanisms? After delivery, MOs are crucial in removing senescent uterine cells to preserve postpartum uterine activity, which helps to maintain the likelihood that a second pregnancy would be successful. Nature , — Rubio-Azpeitia E, Andia I. |
| Rejuvenation Therapy – An Overview of Anti-Aging Stem Cell Therapies | Cellular therapie for Wrestling nutrition supplements regeneration is devoted thedapies the Benefits of rehydration of tissue-specific Wrestling nutrition supplements function and the regulation microenvironment. Rejuvenation therapies, and Taranjit Singh Rai. Nucleotide excision repair NER defects can also affect nucleosome remodeling, histone ubiquitination, stem cell reprogramming, and transcriptional activation, leading to ageing and developmental abnormalities in mammals. Pei, J. van Rijen, et al. |
| Research Horizons | Rejuvenation therapies, Dehydration prevention. Vesicles RejufenationGlucose supplements Aspirin is a common Wrestling nutrition supplements because it can prolong mouse Rejuvenatoon and promote good ageing in Therappies. Stem cell therapy in a caprine model Carbohydrates with fast digestion osteoarthritis. Old age Senescence aging-associated diseases degenerative diseases negligible senescence Gerontology biogerontology cognitive epidemiology Centenarian supercentenarian research into centenarians Longevity myths Life expectancy Maximum life span Biomarkers of aging. In the case of athletic performance enhancement, in particular in the field of orthopedics, a combinational therapy of stem cell injections and infusions, together with physical therapy, may be the way to go. |
Rejuvenation therapies -
In addition, skin may lose tone, feel less firm and lose the healthy glow that is evident in younger skin. Laser resurfacing, mechanical resurfacing, chemical peels and injectable products can improve the appearance of fine lines and wrinkles of the entire face or those that develop in specific regions of the face, such as the upper lip and around the eyes.
These treatments can also be used to address pigmentation disorders, such as sun and age spots, and they can be used to improve the appearance of acne scars or other skin conditions.
The specific type of treatment that will best address your concerns are determined after a consultation with your board-certified plastic surgeon. Most skin treatments require a series of treatments and a multi-modality approach to achieving excellent results.
Most importantly, the patient must be committed to protecting his or her skin going forward so that the results achieved will be longer lasting. The following are some examples of skin rejuvenation and resurfacing treatment methods:.
Conditions that can be treated with skin rejuvenation and resurfacing. Every patient is unique and will exhibit different combinations of genetic and environmental signs of aging that impact their skin.
There are multiple ways to treat many of these issues, and those treatment methods should be planned and discussed with your board-certified plastic surgeon based on your specific situation and desires.
The following are some of the conditions that different skin rejuvenation approaches can address:. Many patients undervalue the importance of skin texture, but it is a critical component of a vital-looking face.
The human eye equates smooth skin with youth, sometimes without us even realizing it. American Society of Plastic Surgeons. Rejuvenation technology and its effects on individuals and society have long been a subject of science fiction.
The Misspent Youth and Commonwealth Saga by Peter F. Hamilton are among the most well known examples of this, dealing with the short- and long-term effects of a near perfect year-old to year-old body change with mind intact.
The less perfect rejuvenation featured in the Mars trilogy by Kim Stanley Robinson results in long-term memory loss and sheer boredom that comes with extreme age. The post-mortal characters in the Revelation Space series have long-term or essentially infinite lifespans, and sheer boredom induces them to undertake activities of extreme risk.
Aging is the accumulation of damage to macromolecules , cells , tissues and organs in and on the body which, when it can no longer be tolerated by an organism , ultimately leads to its death. If any of that damage can be repaired, the result is rejuvenation.
There have been many experiments which have been shown to increase the maximum life span of laboratory animals, [ citation needed ] thereby achieving life extension.
A few experimental methods such as replacing hormones to youthful levels have had considerable success in partially rejuvenating laboratory animals and humans. A experiment involved breeding genetically manipulated mice that lacked an enzyme called telomerase, causing the mice to age prematurely and suffer ailments.
When the mice were given injections to reactivate the enzyme, it repaired the damaged tissues and reversed the signs of aging. human growth hormone HGH ; 2.
erythropoietin EPO ; 4. insulin; 5. DHEA ; 6. melatonin; 7. thyroid; 8. In theory, if all or some of these hormones are replaced, the body will respond to them as it did when it was younger, thus repairing and restoring many body functions.
In line with this, recent experiments show that heterochronic parabiosis , i. connecting the circulatory systems of young and old animal, leads to the rejuvenation of the old animal, including restoration of proper stem cell function.
Similar experiments show that grafting old muscles into young hosts leads to their complete restoration, whereas grafting young muscles into old hosts does not.
These experiments show that aging is mediated by systemic environment, rather than being an intrinsic cell property. Most attempts at genetic repair have traditionally involved the use of a retrovirus to insert a new gene into a random position on a chromosome.
But by attaching zinc fingers which determine where transcription factors bind to endonucleases which break DNA strands , homologous recombination can be induced to correct and replace defective or undesired DNA sequences. The first applications of this technology are to isolate stem cells from the bone marrow of patients having blood disease mutations , to correct those mutations in laboratory dishes using zinc finger endonucleases and to transplant the stem cells back into the patients.
Enhanced DNA repair has been proposed as a potential rejuvenation strategy. Stem cell regenerative medicine uses three different strategies:. A salamander can not only regenerate a limb , but can regenerate the lens or retina of an eye and can regenerate an intestine. For regeneration the salamander tissues form a blastema by de-differentiation of mesenchymal cells , and the blastema functions as a self-organizing system to regenerate the limb.
Yet another option involves cosmetic changes to the individual to create the appearance of youth. These are generally superficial and do little to make the person healthier or live longer, but the real improvement in a person's appearance may elevate their mood and have positive side effects normally correlated with happiness.
Cosmetic surgery is a large industry offering treatments such as removal of wrinkles "face lift" , removal of extra fat liposuction and reshaping or augmentation of various body parts abdomen , breasts , face.
There are also, as commonly found throughout history, many fake rejuvenation products that have been shown to be ineffective.
Chief among these are powders, sprays, gels, and homeopathic substances that claim to contain growth hormones. Authentic growth hormones are only effective when injected, mainly due to the fact that the amino acid protein is too large to be absorbed through the mucous membranes , and would be broken up in the stomach if swallowed.
The Mprize scientific competition is under way to deliver on the mission of extending healthy human life. It directly accelerates the development of revolutionary new life extension therapies by awarding two cash prizes: one to the research team that breaks the world record for the oldest-ever mouse; and one to the team that develops the most successful late-onset rejuvenation.
Current Mprize winner for rejuvenation is Steven Spindler. Caloric restriction CR , the consumption of fewer calories while avoiding malnutrition, was applied as a robust method of decelerating aging and the development of age-related diseases.
The biomedical gerontologist Aubrey de Grey has initiated a project, strategies for engineered negligible senescence SENS , to study how to reverse the damage caused by aging. He has proposed seven strategies for what he calls the seven deadly sins of aging: [16]. During the ageing process, fibroblasts lose contractility and exhibit an unbalanced production and degradation of ECM proteins, ultimately leading to reduced connective tissue stiffness and even age-related diseases.
Senescent cells SCs comprise a heterogeneous cell population because of their various cell-autonomous activation pathways and microenvironmental circumstances.
Although cell-cycle arrested, SCs are still metabolically active and can perform various functions of the parent cells. High quantities of SCs secreting chronically SASP are found in aged tissues, causing irreversible reprogramming of their adjacent cells.
Partial reprogramming of SCs can reduce the persistent inflammatory state related to ageing and secondary senescence in surrounding cells by inducing the SASP.
During ageing, the immune system progressively undergoes disorders of immune cell generation, differentiation, and function, leading to a chronically subclinical inflammatory condition. Several studies have proposed that targeting central immunological processes and specific immune subpopulations can reduce specific age-induced immune changes.
Macrophages reside in the bone marrow and are defective in efferocytosis and hyperactivated with ageing. Neutrophils can also function as an anti-inflammatory shift in macrophages by influencing the surrounding microenvironment or controlling the behavior of macrophages during tissue injury.
The senescence in immune cells affects innate and adaptive immunity, particularly natural killer NK cells, B cell, and T cell function, potently driving age-related changes in solid organs.
In vivo reprogramming might be significantly impeded by NK cells, which identify and eliminate partially converted cells in a degranulation-dependent mode.
Some hormones, signaling pathways, cytokines, and growth factors might display T cell reconstitution effects and reduce the negative effects of age-related T cell deficiency.
An in vitro B cell population with youthful characteristics and cellular reactivity to immunological stimulation can be revived after B cell depletion in elderly mice. Many specialized cells with different sources deserve further research for tissue and organ regeneration and rejuvenation.
For example, in the vertebrate retinas, Müller cells serve as the primary supportive and protective glial cells. They can secrete various cytokines and exhibit the potential for self-renew and trans-differentiation into retinal neurons. Targeting β-cell and restoration of function is of vital importance for effective therapeutic strategies.
For instance, the astrocytes and pancreas exocrine cells can be respectively direct reprogrammed into neuroblasts and β-cells via lineage-specific transcription factors. The known role of these signaling pathways is complex and mutually connected.
Given the prominent association of signaling pathways with rejuvenation and ageing, targeting these signaling systems pharmacologically and therapeutically has great potential for rejuvenation and human health Fig. The target signaling pathways for cellular rejuvenation.
Target signaling pathways for cellular rejuvenation are listed according to their biological functions. Many interventions, like dietary restriction and drugs, improve metabolism and extend longevity through nutrient-sensing pathways. In addition, targeting the pathways of damage-induced and developmental senescence can regulate the cell cycle and alleviate age-associated phenotypes.
Modulating many inflammation pathways also provides an effective route to rejuvenation. Nutrient availability is crucial in regulating ageing and rejuvenation in mammals. Meanwhile, the AMPK pathway is a core mediator of energy homeostasis engaged in the pathobiology of ageing and age-linked disorders.
The cell functionality can be hampered by persistent DNA damage, which can also accelerate senescence and apoptosis. Moreover, the alterations in the integrity and efficacy of mtDNA repair contribute to DNA damage accumulation, illness, and ageing. The cytosolic DNA sensor cyclic GMP-AMP Synthase cGAS binds to the effector protein stimulator of interferon genes STING , initiating a DNA sensing signaling pathway for innate immune responses.
There are also a series of systems repairing the DNA, including BER, NER, and double-strand break DSB. Reactive oxygen species ROS are mainly generated from oxidative phosphorylation in mitochondria, and maintain a dynamic balance with antioxidation systems under physiological conditions.
Low ROS levels enhance the defensive mechanisms by producing adaptive responses for stress tolerance and longevity, whereas high ROS levels create insufficient adaptive responses that may accelerate the onset and course of ageing.
Besides, mtDNA is susceptible to damage by mitochondrial ROS. Peroxiredoxins have been shown to facilitate ROS-based redox signaling and to trigger many cellular stress responses.
Metabolic stress, hypoxia, protein damage, and mitochondrial ROS all can impair mitochondrial protein homeostasis and functions. The transcriptional activation program of mitochondrial chaperone proteins and proteases is known as the mitochondrial unfolded protein response UPR mt , which is a mitochondrial response to stress.
Activating transcription factor associated with stress-1 ATFS-1 participates in the upregulation of genes involved in multiple stress response pathways for organismal survival of acute stressors. Meanwhile, in the initial development stages of elderly individuals, age-dependent levels of histone 3 methylation partially influence UPR mt activation.
However, prolonged UPR mt activation might also induce the propagation of mitochondrial damage. Multiple signaling cascades whose integration targets the induction of senescence, ageing, and associated disorders can be activated by the cycle of physiological interactions between inflammation and oxidative stress.
In mammals, the major pro-inflammatory cytokines, which include interleukin-6 IL-6 , tumor necrosis factor-α TNF-α , and IL-1α, significantly remodel the immune system. The NF-κB signaling pathway is highly linked with the initiation and deterioration of tissue inflammation and ageing process. NF-κB can induce pro-inflammatory mediators, SASP, chemokines, and adhesion molecules, and the crosstalk between upstream signaling elements including MAPK, mTOR, and protein kinase B affects the transcriptional activity of NF-κB.
Therefore, these shared pathways might provide a common route to rejuvenation by modulating inflammation, and some distinct pathways have great potential of targeting improving specific functions.
The transforming growth factor beta TGF-β superfamily is a vast protein group, including three TGF-βs TGF-β1—3 , bone morphogenetic proteins BMPs , and growth differentiation factors GDFs.
Many findings on age-related diseases have reported that TGF-β signaling dysfunction or increased levels of TGF-β ligands induce metabolic dysfunction, tissue fibrosis, inflammation, regeneration suppression, and cell degeneration. Meanwhile, ageing also induces many abnormalities at the TGF-β receptor level.
TGF-β signaling possesses dual functionality and versatility in some age-related disorders and cancer as a suppressor and a promoter.
TGF-β signaling can regulate matrix protein synthesis and matrix degradation, and alter cell-cell interaction.
TGF-β overexpression results in ECM deposition, epithelial—mesenchymal transition EMT , and cancer-associated fibroblast CAF formation, then leading to fibrosis and cancer. For preservation and transition from the pluripotent state during embryo development, stem cells need β-catenin to moderate the response to Wnt signaling.
Increased Wnt signaling has been found in aged organisms and excessive levels of Wnt are damaging to organism functionality. iPSC reprogramming is widely defined as the rejuvenation of mature differentiated cells to an embryonic-like fate. The transcriptome, epigenome, and metabolome of differentiated cells can be significantly altered by the transient expression of Yamanaka factors OCT4, SOX2, KLF4, and cMYC; OSKM , which can also remodel the cells into iPSCs.
But in distinct subpopulations of fibroblasts, the change of fibroblast component and the level of secreted inflammatory cytokines might affect the in vitro reprogramming effectiveness and in vivo wound healing rate. The iPSC reprogramming technique has extensive potential for molecular regeneration, disease modeling, and drug discovery.
The somatic cells of elderly donors can be utilized to generate human iPSCs, and cell reprogramming can reverse the key signs of ageing. By lengthening telomeres, reorganizing the mitochondrial network, alleviating oxidative stress, and recovering pluripotency, the reprogramming process transforms aged cells into young condition.
Telomere malfunction and chromosomal fragility can impair the ability of iPSCs to self-renew and the developmental pluripotency to differentiate.
Moreover, in the cells with telomere and mitochondria defects, somatic cell nuclear transfer SCNT -mediated reprogramming might be a better technology than current reprogramming factors. In addition, iPSCs can be reprogrammed from patient cells via small molecules, miRNAs, and combinations of reprogramming factors, and be differentiated into somatic cells for drug testing and regenerative medicine.
However, many studies clarified that ageing also might constitute critical barriers to cell reprogramming due to cellular senescence, inflammation, telomere reduction, and metabolic alterations.
The differentiated cells or premature termination of reprogramming can also carry the gene mutation and the full genetic heritage of the patient, which might contribute to long-term risk and tumor formation.
Studies have proved that some longevity-promoting compounds and inhibition of age-related pathways enhance reprogramming in regenerative therapy. There are also many methods to boost the safety of iPSCs, such as using suicide genes to eradicate any undifferentiated iPSCs that remain after therapy, choosing younger donors, using appropriate cell sources, improving gene delivery techniques, replacing DNA delivery with proteins, mRNA, or regulatory miRNAs, using small-molecule DNA modifiers, and using low-passage iPSCs.
Lineage reprogramming, also described as direct reprogramming, is the procedure of switching somatic cells from one lineage to another with no transition for intermediate pluripotent states. For instance, recent research demonstrated that certain pro-neural transcription factors can directly reprogram non-neural somatic cells into neurons, skipping the pluripotent stage.
Meanwhile, because of the unique advantages of in situ conversion in live organs, lineage reprogramming is efficient and suitable for in vivo tissue repair and rejuvenation. Direct reprogramming in vivo may also benefit from minimizing hazards for genetic changes during prolonged in vitro culture, cancer development associated with de-differentiation, and immunological rejection following transplantation.
The senescent program induced by ageing process and tissue damage can offer a beneficial microenvironment for in vivo lineage reprogramming.
Chiche et al. suggested that tissue damage induced senescence and SASP secretion to promote the plasticity of resident cells, promoting in vivo reprogramming in tissue repair and regeneration.
This technology can be built to utilize numerous and convenient autologous patient-derived cell types as a source, and is particularly crucial to replicate age-related traits and mimic the onset pathophysiology of diseases. Cell reprogramming is a stepwise protocol.
Studies have proved that somatic cell reprogramming mediated by OSKM for fewer than 7 days induced transient cellular alterations and reversible dysplasia, but partial reprogramming induction for more than 7 days could lead to tumor formation.
The cellular re-differentiation to the original phenotype with epigenome rejuvenation and the ability to react to optimum cocktails of certain differentiation factors is the representative feature of partial reprogramming.
Generally, it is difficult to distinguish between the underlying epigenetic alterations that rejuvenate ageing cells and the changes that regulate the shift in cellular identity. Partial reprogramming is able to restore the common features of cellular ageing without altering the identity or function of the cells.
Chondronasiou et al. demonstrated that partial and reversible reprogramming could improve the ageing states in cells, increase the ability of old mice to restore tissue damage, and lengthen the lifespan of progeroid mice.
Epigenetic remodeling is associated with biochemical modifications to the genome, leading to an altered response of gene transcription to physiological stimuli.
DNA methylation clocks might detect a wide range of ageing-related epigenetic modifications that are indicative of genomic, cell biological, and tissue changes that occur during life. Protein-protein interactions can induce allosteric regulatory sites in complicated epigenetic machinery.
During reprogramming without de-differentiation, the mobility of heterochromatin protein 1β, an essential epigenetic modifier, has been proved to increase in SCs and promote epigenetic rejuvenation.
For epigenetic rejuvenation, distinguishing the rejuvenative features of reprogramming from dedifferentiation is a strong development. Mitochondria role in epigenetic processes mostly involves alterations in DNA methylation, histone modification in nuclear chromatin, and posttranslational gene control by noncoding miRNAs.
Differential mtDNA methylation is associated with various conditions, including ageing and ageing-related diseases, changed metabolism, alterations in circadian rhythm, and even cancer.
Moreover, the conserved histone lysine demethylases JMJD Besides, all metabolic intermediates that serve as substrates or cofactors for epigenetic alterations originate from the Krebs cycle and other mitochondrial metabolic pathways.
Alternate splicing, different promoter or enhancer usage, ncRNAs, and epigenetic changes that impact the structure and function of chromatin all can modulate transcription.
Retrotransposon-mediated promoters might also promote gene regulation and expand protein diversity for phenotypic variation and embryo development. During ageing, heterochromatin decay might upregulate the level of silent retrotransposons, leading to promoted mobility of retro-transposable elements RTEs within genomes and cellular homeostasis disruption.
In nascent RNAs of human cells, m 6 A actively regulates the expression level of both autonomous LINEs and co-transcribed LINE relics, facilitating the retrotransposition of LINE. The inflammatory response can trigger epigenetic alterations, and epigenetics in turn can interfere with inflammation action.
In reaction to severe inflammatory events, transitory activation of NF-κB-related innate immunity and senescence-related inflammatory elements might enhance reparative cellular reprogramming. DNA methylation and histone acetylation are correlated with TNF-α expression during development and inflammatory disorders.
For instance, Sera et al. found that the X-chromosome-specific enzyme, UTX, maintained the expression of downregulated genes during ageing via demethylase-dependent and -independent epigenetic modulation, contributing to hematopoietic homeostasis and inflammation regulation.
Ageing is unavoidably accompanied by a diminished capacity to maintain tissue integrity and function. Cell or tissue rejuvenation without dedifferentiation is known as epigenetic rejuvenation, and it leads to a more youthful functional state and reversed ageing molecular markers.
In addition, epigenetic modifications can target several druggable pathways. In addition, senotherapy can increase lifespan, restore the functionality of bone marrow, muscle, and skin progenitor cells, enhance vasomotor function, and decrease the onset of atherosclerosis. Mitochondria is responsible for the ATP production required for organisms and apoptosis, autophagy, the creation of iron-sulfur clusters, amino acid synthesis, copper and lipid metabolism.
Conversely, the disturbed mitochondrial dynamics, like genetic ablation of mitochondrial fusion and fission components, also cause metabolic changes. Age-related disruption in energy balance and an increased propensity for age-related illnesses may be caused by the reduction in mitochondrial activity.
The crosstalk between mitochondria and other organelles like lysosomes might also lead to increased oxidative stress, reduced ATP production, and breakdown of cellular catabolic mechanisms, ultimately inducing metabolic imbalance and ageing.
The mitochondrial functions in energy homeostasis and metabolism are closely associated with protein quality control factors in disease and age-related disorders, such as PTEN-induced putative kinase 1 PINK1 , Parkin, and TNFR-associated protein 1 TRAP1.
Mitochondria also segregate many critical metabolic pathways, like the TCA cycle, fatty acid β-oxidation, and the one-carbon cycle. The synthesis of mitochondrial metabolites in these pathways might be involved in additional mechanisms that control stem cell activity and fate decisions.
The Mitophagy pathway functions as a crucial mitochondrial switching that guides bioenergetic transition and metabolome remodeling attributes, to eventually define the effectiveness and quality of nuclear reprogramming and stemness transition in somatic cells.
Thus, mitochondrial targeting or mitophagy regulation can promote metabolic remodeling, playing potential roles in rejuvenation and regeneration. Deregulation of the redox state causes a rise of peroxides, ROS, and free radicals, which are collectively known as oxidative stress.
Adaptive cellular responses to pathogenic challenges in ageing and age-associated disease tolerance, such as ischemia tolerance, can also be greatly benefited by moderate oxidative stress caused by diverse stressors.
It has been demonstrated in numerous human cohorts and animal experiments that oxidative damage and inflammation might promote a state of susceptibility and raise the possibility of unfavorable health outcomes. For oxidative damage regulation, bioactive exosomes have antioxidant effects on reducing the excessive ROS, promoting intracellular anti-oxidative stress defense, immunomodulation by blocking excessive ROS and changing mitochondrial function.
There are some promising antioxidant or anti-inflammatory substances, like minerals, vitamins, fatty acids, and antioxidant phytochemicals, to postpone skeletal muscle ageing and the onset of sarcopenia. Autophagy is a conserved, physiologic, and self-protective mechanism that supports cellular homeostasis and stress adaption.
Autophagosomes with bilayered membrane vesicles can capture the degraded cellular components and subsequently merge with the lysosome to digest long-lived proteins, excess or damaged organelles, and misfolded or aggregation-prone proteins.
Depending on the selective autophagic degradation of several organelles, autophagy is subdivided into mitophagy, aggrephagy, pexophagy, reticulophagy, nucleophagy, lysophagy, xenophagy, lipophagy, ferritinophagy, and glycophagy.
Autophagy serves as one of the central pathways in the protection against functional loss and increased vulnerability to ageing process and age-related disorders.
The activity of autophagy and the autophagy gene transcription by specific transcription factors, epigenetic changes, and microRNAs have emerged as crucially conserved pathways for promoting lifespan. Enhancing the function of the autophagy-lysosome system can eradicate age-related organelle degeneration, which might have regenerative benefits for cellular rejuvenation.
The molecular circadian oscillator consists of transcriptional and translational feedback loops that are interlocked. BMAL1 and CLOCK or NPAS2 have the ability to heterodimerize and bind to E-box elements of many clock-controlled genes to drive transcription.
As PER and CRY degrade over the night, negative regulation of BMAL1 and CLOCK is released, allowing the beginning of a new circadian day.
In addition, the molecular clock controls the rhythmic expression of genes related to numerous cellular processes and nutrient-sensing pathways, which provides feedback to the primary clock system. Almost all the major genes implicated in the modulation of the circadian cycle have been found to induce alterations in circadian rhythms in their absence and to have an impact on health status.
Thus, improving intracellular synchronization and the synchronization between SCN network and central and peripheral clocks might restore accuracy and stability to the ageing circadian system. Melatonin, produced in the pineal gland and mitochondria, participates in complicated intracellular signaling pathways with anti-ageing, antioxidant, chemopreventive, immunostimulatory, and tumor-inhibitory functions.
Stem cells contain a functional circadian clock whose rhythmicity contributes to the multipotent cell properties in constant renewal and injury response.
Multipotent stem cells from various organs also have distinct clock gene expression profiles with various amplitude ranges. Histone alterations, DNA modifications, non-coding RNAs, huge multisubunit chromatin remodeling complexes, and additional epigenetic changes are also significant points in the circadian modulation of stem cell destiny.
With ageing, stem cells receive signals from endogenous and external factors operated through circadian rhythms and epigenetic clocks. The circadian output and oscillator system have adapted to the particular homeostatic requirements of the adult stem cell region in the young organism.
But the circadian functions of ageing stem cells might switch toward a stress-dominated program. found that the overexpression of CLOCK could rejuvenate physiologically and pathologically aged human MSCs. Hence, circadian clock regulation provides opportunities to rejuvenate stem cells for various tissue engineering approaches.
The oscillations of peripheral clocks in numerous peripheral tissues, including the heart, liver, adipose tissue, retina, and multiple brain regions, can be controlled by synchronizing the circadian clock produced by SCN neurons. Cell-autonomous circadian oscillations also have a substantial impact on the physiology and pathology of peripheral organs.
Many studies have suggested that circadian rhythms might be in a noticeably different phase during development in one cell or tissue type compared to another part of the body.
These alterations in tissue-specific clocks might affect immune hyperactivation with ageing. Besides, tissue susceptibility and reactions to toxicity also change during the circadian cycle, which indicates the development of drug timing administration. The molecular mechanisms that mediate cellular and organ ageing provide therapeutic targets for cellular rejuvenation.
The increasingly rejuvenative approaches have been developed, and the schematic overview of strategies for cell rejuvenation is shown in Fig.
It contains cellular reprogramming, clearance of SCs and SASP inhibitor, metabolic manipulation, the restoration of aged stem cell function, microenvironment remodeling, resetting the circadian clock, immune rejuvenation, and heterochronic parabiosis.
Especially, cellular reprogramming can rejuvenate the terminally differentiated cells to the pluripotent state or epigenetically unstable intermediates, and also to another desired cell type for tissue repair.
The reprogramming technology mainly includes iPSCs, partial reprogramming, and direct reprogramming Fig. Schematic overview of strategies for cell rejuvenation.
Various strategies have been developed for cell rejuvenation that leverage intrinsic and extrinsic factors, including epigenetic reprogramming, genetic enhancement, autophagy modulation, and metabolic manipulation. Furthermore, small molecules, growth factors and cytokines, blood factors, iPSC technology, clearance of senescent cells and SASP, microenvironment regulation, and circadian clock modulation can also exert great influences on cell rejuvenation.
iPSCs induced pluripotent stem cells, SASP senescence-associated secretory phenotype. Reprogramming approaches for rejuvenation. The iPSC-mediated cell reprogramming is a protocol that somatic cells are first dedifferentiated into iPSC and then differentiated into the desired somatic cells.
Partial reprogramming refers to a short exposure to Yamanaka factors only generates intermediates with high plasticity. Transforming somatic cells from one lineage to another without transitioning through intermediary pluripotent stages is known as direct lineage reprogramming.
The biological age of our cells, tissues, and organs is determined by an epigenetic clock based on alterations in the DNA methylation profile.
A change in permission for future development and a return to a more flexible and pluripotent state are made possible by the removed DNA methylation instruction, and the production of iPSCs can also get around epigenetic constraints and change DNA methylation patterns to support youthful states in cells.
These cells eventually adapted to closely resemble ESCs. iPSCs can be derived from different tissue-specific cell types, such as human endometrial cells, endothelial cells in the placental artery, amnion-derived cells, fibroblast, blood cells, and even cancer cells. Senescent and centenarian cells are revived through pluripotent reprogramming, and the iPSCs produced from these cells have reset telomere length, gene expression profiles, oxidative stress, and mitochondrial metabolism.
Currently, given that each random integration event of a retrovirus poses a possible genetic risk, despite some of these approaches have produced lower efficiency than conventional reprogramming of retroviral administration, they constitute a step closer to therapeutic application.
Using partial reprogramming, the epigenetic age of cells can be reduced without losing cell identity, suggesting that full reprogramming of iPSCs is not necessary to reverse ageing of somatic cells. In vitro cellular reprogramming has observed alleviation of age-associated phenotypes and the reset of age clock.
Due to the physiological complexity of the ageing process, it is necessary to study in vivo reprogramming to gain a deeper understanding of how it can affect cellular and organismal ageing. Ocampo et al. reported that transient cyclic induction of OSKM in vivo ameliorated age-associated hallmarks, extended lifespan in progeroid mice, and promoted tissue repair from streptozotocin-induced pancreatic damage as well as cardiotoxin-caused muscle damage, with no resulting teratoma formation.
For example, expression of OSKM specifically in hepatocytes can dedifferentiate adult hepatocytes into progenitor cells and promote cell proliferation concurrently, and functionally, short-term in vivo reprogramming increases liver plasticity and promotes regeneration.
and the short-term OSKM expression reduces myocardial infarction-induced damage and improves cardiac function. In vivo reprogramming with short-term cyclic expression of OSKM also inhibits the progression of intervertebral disc degeneration IDD , and significantly improves senescence-associated phenotypes in ageing nucleus pulposus cells NPCs.
The first is teratomas, a type of tumor that could be cancerous, which may be attributable to too much OSKM induced by inappropriate dosage. DNA methylation-targeted drugs mainly contain DNA methyltransferase inhibitors, like 5-Azacytidine.
The removal of DNA methylation is a prerequisite for epigenetic rejuvenation and the generation of iPSCs. BETi has exhibited the effect to induce keratinocytes dedifferentiation, to enhance the migratory ability in keratinocytes in vitro, and to promote skin wound healing in vivo.
The 3-deazaneplanocin A DZNep compound, which specifically inhibits H3K27me3 and H4K20me3, is crucial for activating OCT4 during iPSC reprogramming. HDAC inhibitors have the ability to reverse the deacetylation of histone tails and trigger the expression of specific genes.
Recent advances in our understanding of gene manipulation against age and age-related diseases have prompted several distinct interventional strategies. The first one is the repression of senescence-associated genes to delay or reverse senescence.
For example, identifying the driving role of the histone acetyltransferase gene KAT7 in senescence in the Werner syndrome WS and Hutchinson-Gilford progeria syndrome HGPS models via genome-wide CRISPR-Cas9-based screening.
Analysis of proteomic and transcriptomic datasets revealed senescent cell antiapoptotic pathways SCAPs , covering Bcl-2 family members, ephrins, PI3K isoforms, p21CIP1, HIF-1α, and plasminogen-activated inhibitors 1 and 2 PAI-1 and -2 , were indeed more highly expressed in senescent than non-senescent cells, which is responsible for the resistance of SCs to apoptosis.
Furthermore, the dominant SCAPs also vary with different cell types, which expands the limitations of genetic silence of SCAPs to remove SCs. Genetic strategy against senescence also can be achieved by overexpression of longevity gene to reset gene expression in SCs.
Telomerase reverse transcriptase TERT and follistatin FST gene therapy using high-capacity cytomegalovirus vector by intranasal inhalation or injection significantly improved phenotypes associated with healthy ageing and extended lifespan in mice without severe side effects.
Further, TERT reduced the telomere shortening associated with ageing, and both therapies halted the degeneration of the mitochondrial structure. gov in the world NCT Another study reported the gene therapy with three longevity genes FGF21, sTGF-βR2, and αKlotho treated multiple age-related diseases.
The association between SCs burden and health span helps to discover chemicals that selectively remove senescent cells. The fact that SCs exhibit resistance to apoptosis supports the idea that these SCs rely on antiapoptotic, pro-survival mechanisms to prevent self-destruction.
Based on bioinformatic analysis, forty-six compounds that target SCAP pathways have been identified as possibly senolytic. D has the ability to trigger apoptosis brought on by dependency receptors, like as ephrins, in part through blocking Src kinase.
For example, senescent human pre-adipocytes or MSCs are susceptible to D but not Q or F, while senescent HUVECs are susceptible to Q or F but not D. Navitoclax ABT , a potent antagonist of BCL-2 and BCL-xL, eliminates senescent myocytes and hematopoietic stem cells but not senescent pre-adipocyte.
albeit not senescent human pre-adipocytes. Despite the apoptotic SCs induced by senolytic strategies, such apoptotic cells are still finally removed by the immune system.
NK cells, macrophages, and cytotoxic T cells are innate and adaptive immune cells that carry out immunosurveillance of SCs and play a crucial role in their elimination when they are young or under physiological conditions.
The interaction between the activating NKG2D receptor and its ligands expressed on SCs determines the involvement of NK cells in the elimination of SCs. In cycling human endometrium, decidual senescence is required to support embryonic implantation, and acute decidual senescence can promote the release of IL and attract uterine NKs, further selectively targeting and clearing senescent decidual cells through the interaction of NKG2D and DNAM1 receptors-mediated granule exocytosis.
After delivery, MOs are crucial in removing senescent uterine cells to preserve postpartum uterine activity, which helps to maintain the likelihood that a second pregnancy would be successful.
Accumulating evidences have demonstrated that SCs could be cleared by immune cells, which could be a lever for lowering the burden of SCs.
Suppressing the SASP also has been an alternative strategy for combating cellular senescence-associated phenotypes or diseases. p38MAPK is the MAPK family member and also an important regulator of the SASP, and p38MAPK inhibitors including SB, UR, and BIRB , potently suppressed SASP expression in SCs.
Of note, unlike the intermittent administration of senolytic drugs, most SASP inhibitors are needed to maintain suppression of SASP in a manner of continuous treatment, which raises the likelihood of side effects compared to senolytics taken on an intermittent schedule.
The metabolic disturbance is known to drive the function decline of adult stem cells with respect to ageing, and the mechanism by which nutrient-sensitive signaling pathways such as the mTOR and AMPK pathways play a central role.
Long-term 1 year rapamycin treatment increased memory and learning in both young and old mice, but it also improved some of these traits in young animals, suggesting that rapamycin has beneficial effects that are age-independent.
Metformin also contributes to metabolic-induced rejuvenation by regulating nutrient-sensitive signaling. elegans by activating AMPK in a LKB1-dependent mechanism.
To maintain genomic integrity and tissue homeostasis, adult tissue-specific stem and progenitor cells have defensive mechanisms that reduce endogenous DNA damage. However, the DNA repair response in stem cells declines with ageing, which results in the loss of stem cell properties and DNA damage-caused cellular senescence and organ atrophy.
In telomere-dysfunctional animals, administration of the NMN preserves telomere length, inhibits the DNA damage response and p53, enhances mitochondrial activity, and reverses liver fibrosis. The conducive effect of proteostasis loss on stem cell ageing inspires the strategy of protein homeostasis to protect stem cell function.
Numerous chemical chaperones, including 4-Phenylbutyric Acid 4-PBA and its derivatives, have been shown to exhibit anti-amyloidogenic activity and to prevent misfolding protein aggregation. By increasing partially folded proteins and stabilizing their more compact native structures, 4-PBA can reduce the formation of unfolded aggregates and increase the pool of folding intermediates.
It can also change the structure of Hsps to increase the exposure of hydrophobic surfaces, which improves Hsp chaperone activities. The depletion of adult stem cell pool with age contributes to tissue degeneration, so maintaining tissue homeostasis into old age requires replenishing the stem cell pools.
Stem cell transplantation is a therapeutic intervention, and it has been extensively researched as a way for the replenishment of regenerative cells to provide stem cells from an unaffected donor or gene-corrected autologous cells to the recipient.
A large number of adult stem cells are available for autograft or allograft therapy, but only HSCs transplantation is widely accepted and used clinically, which has been demonstrated to be successful in treating hematologic disorders such as leukemia and lymphoma. For example, EpSCs transplantation can regulate inflammation response, remodel the microenvironment of skin wounds, recapitulate tissue integrity and promote diabetic wound healing.
More importantly, transplanted MuSCs also accessed the satellite cell compartment, replenishing the endogenous stem cell pool and taking part in injury repair. It may be worthwhile to pursue methods for reactivating residual stem cells or combining such procedures with stem cell transplantation.
For instance, inhibition of the p38 MAPK signaling pathway in endogenous MuSCs can rescue muscle regeneration ability in ageing animals. The mechanism by which is in a manner of MDM2-dependent p53 degradation. A recent clinical trial reported implantation of iPSC-derived dopaminergic progenitors into the putamen left hemisphere followed by the right hemisphere of a patient with PD indeed improved clinical symptoms of PD after surgery.
Physiologically, extracellular signaling molecules are cues, such as EVs, neurotransmitters, growth factors, hormones, and cytokines, designed to transmit specific information to target somatic cells or adult stem cells.
EVs function as a cutting-edge tool for stem cell rejuvenation because of their ability to transfer genes safely and with systemic effects. For instance, ESC-EVs can directly facilitate pressure ulcer repair in ageing mice through the rejuvenation of tissue-resided senescent endothelial cells.
Injured tissue has a hostile environment, including inflammation, immune impairment, hypoxic stress, and poor blood supply, which degrades stem cell function, promotes cellular senescence, and results in a low survival rate of transplanted stem cells in vivo.
Therefore, it is essential for stem cells to remain viable and maintain their potency before inducing a strong repair response. The optimization of the culture environment, such as hypoxic pretreatment, may achieve preconditioning-induced protection for stem cells.
Particularly, ESCs require low oxygen levels to survive, which start at embryonic implantation and last throughout fetal development. Adult stem cells such as HSCs and BMSCs, similarly live in hypoxic conditions in vivo.
For example, integrin receptors-mediated cell adhesion to the ECM is necessary for cell cycle progression, particularly during G2 to M transition and early mitosis. Through the process of mechano-transduction, these mechanical cues are transformed into biochemical signals that affect immune cell functions such as cell activation, cytokine generation, metabolism, proliferation, and trafficking.
ECM molecules are continuously produced and secreted throughout life, in both physiologically healthy and pathological states, and they regulate a wide range of biological functions, including stem cell differentiation, angiogenesis, innervation, and wound healing.
Because ECM has a more favorable pro-remodeling host immune response and can offer a natural, instructional microenvironmental habitat for functional tissue remodeling, ECM-based biomaterials have been emerging and exhibit great variability.
Intercellular communication has double-edged—sword activities, contributing to tissue homeostasis maintenance but also detrimental in ageing and related diseases, and altered intercellular communication has been the hallmark of ageing.
The dominant role of inflammation in ageing-related intercellular communication raises the potential of anti-inflammatory agents in lifespan.
Aspirin is a common example because it can prolong mouse life and promote good ageing in humans. Correspondingly, GnRH treatment rejuvenates ageing-impaired neurogenesis and prevents ageing development. The use of DR, including time-restricted feeding TRF and calorie restriction CR , has many profound beneficial effects on ageing through the regulation of circadian clock.
It has been reported that the duration of two months for CR intervention in early life could enhance the amplitude of core clocks in liver. A functional circadian clock system is necessary for CR-mediated lifespan extension, as evidenced by the fact that CR fails to extend the lifespan of BMAL1 knockout mice.
Circadian clock-associated genes modulate the extrinsic and intrinsic mechanisms in lifespan modulation and organ ageing. The circadian clock in intervertebral discs IVDs is functional and temperature-entrainable, and ageing disrupts the circadian rhythm of IVDs in an inflammation-dependent manner and leads to IDD.
Numerous parts of human physiology are regulated by the circadian rhythm, opening up windows for interventions that can be made by only giving medications when their targets are at the proper expression level to rescue. There is growing interest in developing small molecules that directly target the circadian system for medicinal benefits.
KL specifically interacts with CRY, which prevents ubiquitin-dependent degradation of CRY, leading to extending circadian time. Immune system is interconnected with all the other systems in the body, and this systemic nature provides the potential opportunity that targeted modifications to a small group of cells e.
As the origin of blood cell lineages, HSCs are multipotent precursors population that can reconstitute the hematopoietic system and sustain immune homeostasis.
Ageing HSCs have less self-renewal activity, fewer cell divisions, decreased homing efficiency and myeloid lineage-biased differentiation as well as reduced output of lymphoid progenitors. HSCs ageing is accompanied by alterations at the gene level, and genetic modulators by ablation of genes driving ageing or overexpression of rejuvenative genes might be strategies to prevent HSCs dysfunction, such as the deletion of the imprinted gene Grb10 or forced expression of Satb1.
For example, supplementing elderly mice with a sympathomimetic that specifically targets the adrenoreceptor β3 β3-AR agonist, BRL greatly improved the in vivo function of aged HSCs. Immune lineage-mediated cellular rejuvenation mainly focuses on the restoration of T lymphocytes exhaustion caused by organismal ageing, due to its high susceptibility to ageing-associated changes to the immune system.
Preclinical results have shown that proT cells could effectively engraft involuted ageing thymuses, achieve rapid long-term thymic reconstitution and accelerate T cell recovery. Therefore, ProT cells avoid the clinical concerns brought on by graft-versus-host disease GVHD , and it provides an alternative cell-based strategy to rejuvenate T-cell immunity clinically.
As the key site of T lymphopoiesis, the thymus orchestrates adaptive immune responses, and ageing-associated thymic atrophy or involution contributes to adaptive immune system deviations. Cellular reprogramming provides an alternative avenue for thymus function restoration and immune rejuvenation.
Chemical activation of thymus organogenesis program can direct human ESCs to differentiate into thymic precursor lineage, further promoting functional regeneration of human thymus in vivo.
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