Translational Geroscience Strategies for Delaying Multimorbidity

Abstract

The global rise in aging populations emphasizes an urgency to mitigate the escalating burden of chronic age-related diseases. This review discusses advances in geroscience to reframe aging as a modifiable risk factor rather than an inevitability. It explores emerging interventions that hold promise to delay or prevent multiple age-related pathologies concurrently by targeting conserved biological drivers of aging, genomic instability, epigenetic dysregulation, mitochondrial dysfunction, and stem cell exhaustion. Innovations in senolytics and epigenetic reprogramming exemplify transformative strategies to shift the medical paradigm from treating individual diseases to extending healthspan. Critical challenges in translation are addressed, including inconsistent intervention efficacy across species, safety concerns in cellular reprogramming, and ethical debates over prioritizing life versus health span. The review highlights sex-specific disparities in therapeutic outcomes and encourages precision-based approaches to ensure equitable benefits. This review further details a multidimensional roadmap to compress morbidity and redefine healthy aging by leveraging complex tools such as artificial intelligence-driven drug discovery, organ-on-a-chip models, and multiomics integration. It calls for stronger integration of mechanistic discoveries into clinical practice to promote a paradigm of aging balanced on resilience and vitality rather than decline.

The global population is undergoing an unprecedented demographic shift, with individuals aged 60 and older set to double to 2.1 billion by 2050, accounting for over 20% of humanity. According to the World Health Organization, 80% of this cohort will experience at least one age-related chronic condition. − The societal burden of this “silver tsunami” is staggering, as dementia alone incurs annual costs exceeding $1 trillion, whereas age-related disabilities strain healthcare systems and economies worldwide. This crisis stimulated a paradigm shift in biomedical research, transforming aging from an inevitability into a modifiable risk factor. Early 20th-century views of aging as passive “wear and tear” provided a way for geroscience in the discovery of conserved molecular pathways that regulate longevity. − Foundational milestones such as Leonard Hayflick’s concept explained modern replicative senescence, Cynthia Kenyon’s work on Caenorhabditis elegans, and Judith Campisi’s characterization of senescence-associated secretory phenotype (SASP) revealed aging as a flexible process. Recent advances, e.g., partial epigenetic reprogramming to reverse cellular aging and senolytic therapies that eliminate senescent cells, emphasize the potential to decelerate aging itself rather than merely treat its symptoms. −

Currently, aging is understood as a multifactorial process governed by consistent genomic instability, mitochondrial dysfunction, and proteostasis loss to erode cellular resilience, whereas telomere attrition triggers DNA damage responses, propagating epigenetic alterations, and stem cell exhaustion. − Moreover, these mechanisms do not function alone. For example, mitochondrial-derived reactive oxygen species (ROS) accelerate telomere shortening, which in turn activates p53-mediated senescence and may create a vicious cycle of decline. − Crucially, these pathways underpin major age-related diseases. For example, inflammaging (chronic low-grade inflammation) driven by SASP factors (e.g., IL-6 and TNF-α) exacerbates Alzheimer’s (AD) pathology and atherosclerosis, whereas dysregulated nutrient-sensing pathways (e.g., mTOR overactivation) contribute to cancer and metabolic syndrome. , This mechanistic overlap presents a transformative opportunity by targeting aging itself through senolytics, NAD⁺ boosters, or caloric restriction mimetics, which could delay or prevent multiple diseases simultaneously, as championed by initiatives like the Targeting Aging with Metformin (TAME) trial. −

Despite remarkable progress, critical unmet clinical needs persist. Why do interventions, e.g., rapamycin, extend lifespan in mice yet show mixed results in human healthspan? Can epigenetic reprogramming safely reverse aging without oncogenic risks? This review discusses translational strategies, e.g., next-generation senotherapeutics and organoid-based disease models. Here, we discuss controversies, including the antioxidant paradox and ethical dilemmas posed by lifespan extension, and highlight innovative approaches like CRISPR-engineered chimeric antigen receptor (CAR)-T cells for senescent cell clearance. By bridging basic science with clinical innovation, this review aims to provide a path toward compressing morbidity and redefining healthy aging in an unprecedented longevity era.

Emerging Mechanisms of Aging

Telomere Biology beyond Telomerase

Telomeric repeat-containing RNA (TERRA) emerged as a central regulator of telomere stability in aging and age-related pathologies. − TERRA rewrites heterochromatin assembly by recruiting chromatin modifiers, e.g., SUV39H1, to establish H3K9me3 marks, which are essential in silencing recombination-prone telomeric regions. − Beyond structural roles, TERRA forms RNA–DNA hybrids at telomeres, contributing to replication stress and recombination in ALT cells, which can be mitigated by helicases and factors, e.g., FANCM. , In Werner syndrome, WRN deficiency can impair TERRA-mediated R-loops, resulting in replication fork stalling, telomere instability, and accelerated cellular senescence. − Studies further link TERRA dysregulation to broader aging contexts, as elevated TERRA levels in aged human fibroblasts are correlated with heterochromatin erosion and mitochondrial dysfunction, suggesting cross-talk between telomere biology and metabolic aging pathways. , These insights position TERRA not only as a biomarker of telomere dysfunction but also as a potential therapeutic target. For example, antisense oligonucleotides targeting TERRA in Werner syndrome models may reduce genomic instability and explore translational opportunities to mitigate aging-associated telomere damage.

Age-related destabilization of the shelterin complex drives genomic instability and tissue decline. TRF2 is a core shelterin component that prevents ATM activation by folding telomeres into protective t-loops, whereas POT1 sequesters single-stranded DNA to block ATR signaling. − Declining telomere protection, including reduced TRF2 and POT1 function, correlates with telomere deprotection, leading to chromosomal fusions, senescence, and inflammation through cGAS-STING activation. , Notably, shelterin destabilization intersects with diseases beyond cancer, as compromised TRF2 function in cardiomyocytes exacerbates oxidative stress and cell death, whereas POT1 loss in hematopoietic stem cells drives clonal hematopoiesis. − These findings highlight the systemic role of shelterin in aging and its potential as a multiorgan therapeutic target. Current efforts to develop shelterin-stabilizing compounds in combination with gene-editing approaches to boost endogenous shelterin expression exemplify innovative strategies to counteract telomere-driven aging. −

Furthermore, alternative lengthening of telomeres is a telomerase-independent mechanism reliant on homology-directed repair and is observed in both cancer and aging. Although it is a hallmark of aggressive cancers (e.g., osteosarcoma, glioblastoma), its sporadic activation in noncancerous and aged tissues may enable senescence evasion. − It involves telomeric recombination facilitated by PML bodies and proteins like BLM helicase, but this process is error-prone, generating ultrafine anaphase bridges and chromothripsis-like rearrangements. − In progeroid models, alternative lengthening of telomeres-like activity in telomere-depleted cells exacerbates tissue atrophy by promoting mitotic catastrophe and paracrine senescence. − In normal aging, aberrant activation of alternative lengthening of telomeres-like mechanisms in somatic stem cells may accelerate telomere attrition. This unintentional activation may lead to increased genomic instability, thereby promoting stem cell exhaustion and contributing to age-associated tissue degeneration (Figure ). Recent work reveals these telomeres intersect with mitochondrial dysfunction and mTOR hyperactivation, suggesting metabolic vulnerabilities for therapeutic exploitation. − For example, mTOR inhibitors suppress these telomeres in cancer cells, − raising concerns about their utility in curbing aging phenotypes. Moreover, stabilizing telomeres through shelterin modulation or targeted TERRA interventions could reduce genomic instability in patients, offering potential strategies for preventing cardiovascular and hematopoietic age-related disorders. As these telomeres reshape between cancer immortality and somatic decline, understanding their context-specific regulation offers dual promise, e.g., targeting them to treat cancer and blocking their pathological activation to preserve tissue integrity in aging.

1.

Molecular interplay of telomere biology, epigenetics, and aging. Telomeres are protected by the shelterin complex, with telomere attrition contributing to genomic instability and aging. Epigenetic alterations, including heterochromatin marks, TERRA transcripts, and epigenetic clocks, modulate telomere homeostasis and age-related transcriptional noise. Therapeutic avenues may involve telomerase activation, epigenetic drugs, Yamanaka factors, mTOR/AMPK signaling modulation, and ALT-mediated repair to mitigate hematopoietic stem cell exhaustion, cellular senescence, aging-related diseases, and cancer.

Epigenetic Clocks and Aging Drivers

Second-generation epigenetic clocks (e.g., GrimAge, DunedinPACE, and PhenoAge) refined the precision of biological age estimation by integrating disease-specific biomarkers and mortality predictors. − For example, GrimAge is based on DNA methylation surrogates of plasma protein levels and smoking-related methylation changes and outperforms first-generation clocks in predicting lifespan and age-related conditions. ,− In contrast, DunedinPACE quantifies aging pace by tracking methylation shifts linked to declining organ function and offers novel dynamic insights into how interventions alter aging trajectories. , PhenoAge bridges the gap by correlating epigenetic states with clinical biomarkers (e.g., albumin, creatinine), by capturing both morbidity and mortality risks. , Clinical trials have shown that lifestyle interventions can modulate epigenetic aging markers. For example, caloric restriction has been demonstrated to significantly reduce the DunedinPACE score in humans, indicating a slower pace of aging, but its direct impact on specific epigenetic clocks like DunedinPACE or GrimAge remains to be fully established. Notably, dietary intervention to slow aging trials can be explored to demonstrate a Mediterranean diet to reset PhenoAge by attenuating inflammation-related methylation changes. However, inconsistencies may persist, such as smoking cessation may rapidly impact GrimAge but may show delayed effects on PhenoAge, , which highlights the need for clock-specific interpretation in aging research. Moreover, these tools may reshape clinical end points by emerging as sensitive biomarkers to evaluate geroprotective therapies in real-time.

Partial epigenetic reprogramming using Yamanaka factors (Oct4, Sox2, Klf4-OSK) opened radical avenues to reverse age-related methylation drift without inducing pluripotency. , Thus, in aged mice, cyclic OSK expression may restore youthful DNA methylation patterns, revitalize mitochondrial function, and extend health span. ,,, Transient OSK or chemical reprogramming in senescent human cells reduces epigenetic age and senescence markers, suggesting potential translatability. , However, transient reprogramming risks incomplete dedifferentiation, genomic instability, or teratoma formation in residual stem cell populations. , Recent advances mitigate these risks. For example, omitting c-Myc from the reprogramming cocktail or using pulsatile delivery systems minimizes oncogenic potential. , Critics argue that erasing epigenetic “scars” might also delete adaptive changes, such as immune memory, underscoring the need for targeted approaches. Balancing efficacy with safety remains critical as this field transitions from murine models to human trials to address age-related functional decline without compromising genomic fidelity. Thus, epigenetic clocks provide actionable biomarkers for monitoring biological age and tailoring interventions, enabling precision geroscience approaches in clinical trials to slow aging and assess therapy efficacy.

Mitochondrial Dynamics and Quality Control

Mitochondrial-derived vesicles are specialized cargo carriers that selectively transport oxidized proteins and lipids from damaged mitochondria to lysosomes, serving as a first-line quality control mechanism. Unlike mitophagy, vesicles maintain organelle integrity by removing localized damage. This process relies on the PINK1/Parkin pathway, where PINK1 recruits Parkin to depolarized mitochondrial regions, ubiquitinating substrates that signal vesicle budding. − Aging disrupts vesicle biogenesis, leading to ROS accumulation and damage components that propagate oxidative stress. In Parkinson’s, pathogenic mutations in PINK1 or Parkin impair vesicle formation, allowing neurotoxic aggregates, e.g., α-synuclein accumulate, which is a hallmark of dopaminergic neuron degeneration. Interestingly, studies show that mitochondrial vesicle activity declines in aged human neurons, correlating with lysosomal dysfunction and impaired autophagy flux. Restoring this vesicle production with pharmacological PINK1 activation in aged mice reduces mitochondrial oxidative damage and improves motor function, ,− which highlights their enhancement as a therapeutic strategy in age-related neurodegenerative disorders.

Next, the mitochondrial unfolded protein response is a conserved adaptive signal that reprograms nuclear gene expression to mitigate proteotoxic stress, promoting mitochondrial homeostasis. − Activation of this response is triggered by misfolded protein accumulation or ROS and upregulates chaperones (e.g., HSP-60) and proteases via transcription factor ATF5. In C. elegans, NAD⁺ boosters like nicotinamide riboside (Figure ) activate mitochondrial unfolded protein response through sirtuin signaling, with measurable extension in lifespan. , Similarly, murine models demonstrate that unfolded protein response induction through NAD⁺ precursors improves mitochondrial function in aged skeletal muscle and reduces frailty. However, chronic mitochondrial unfolded protein response hyperactivation may be detrimental, as prolonged stress in aging cells depletes NAD⁺ reserves, exacerbating mitochondrial fragmentation. , Recent advances in tissue-specific modulation, e.g., mitochondrial-targeted antioxidants, highlight their potential to decouple longevity benefits from metabolic trade-offs. Despite the promise, challenges remain in balancing its activity to avoid disrupting the redox signaling essential for adaptive stress responses. Targeting this pathway offers a dual opportunity to enhance proteostasis and delay age-related metabolic decline, provided its activation is contextually controlled. Pharmacologic enhancement of mitochondrial quality control, including NAD⁺ boosters or PINK1 activators, may improve tissue resilience and metabolic function, informing patient-specific therapies for neurodegenerative and metabolic diseases.

2.

Chemical Structures of key geroprotective and senotherapeutic compounds: (a) dasatinib, (b) everolimus, (c) ganetespib, (d) hydroxycitrate, (e) JQ1, (f) metformin, (g) MitoTEMPO, (h) MCC-950, (i) nicotinamide riboside, (j) nicotinamide mononucleotide, (k) Omega-3 fatty acids, (l) navitoclax, (m) RTB101, (n) ruxolitinib, (o) quercetin, (p) spermidine, (q) rapamycin, and (r) urolithin A.

Stem Cells and Niche Dysregulation

Aging disrupts the equilibrium between hematopoietic stem cell quiescence and senescence and drives bone marrow dysfunction. , Quiescent hematopoietic stem cells are maintained by niche-derived Wnt inhibitors and TGF-β and remain metabolically inactive to preserve genomic integrity and long-term regenerative capacity. − In contrast, senescence triggered by DNA damage, oxidative stress, or inflammatory cytokines results in irreversible cell-cycle arrest and a pro-inflammatory secretome that corrupts neighboring cells. − Aging can skew this balance as aged niches overexpress activin A (TGF-β superfamily member), suppressing Wnt signaling and forcing hematopoietic stem cells into premature proliferation, depleting the quiescent pool. − Concurrently, senescence-associated β-galactosidase-positive stem cells accumulate, exacerbating myeloid bias and anemia in elderly populations. Recent studies identify niche remodeling as a central driver of osteolineage cells in aged bone marrow that overproduce granulocyte colony-stimulating factor, which erodes quiescence and amplifies clonal dominance of dysfunctional hematopoietic stem cells. − Therapeutic strategies to restore balance, e.g., neutralizing activin A or delivering Wnt agonists, rejuvenating aged hematopoietic stem cells in murine models, improving engraftment, and reducing leukemia incidence. − Modulating stem cell niches through Wnt agonists or activin A inhibitors may offer clinically actionable avenues to restore hematopoietic function and mitigate age-related anemia and immune dysfunction. These findings underscore the niche role of a rheostat for stem cell fate, offering targets to mitigate age-related hematological decline.

3D organoid systems are revolutionizing the study of stem cell aging by recapitulating tissue-specific niches in vitro. , Brain organoids derived from aged iPSCs reveal that aging neural stem cells exhibit reduced self-renewal due to elevated BMP4 signaling from surrounding astrocytes, mirroring in vivo hippocampal atrophy. − Similarly, aged intestinal organoids demonstrate diminished crypt formation due to increased secretion of Wnt inhibitor Notum by Paneth cells, which impairs Lgr5⁺ stem cell proliferation and mirrors age-associated intestinal decline. − Organoid models enable precise testing of the rejuvenation strategies. In aged animal models and emerging brain organoid studies, the transient expression of Yamanaka factors has been shown to enhance neural stem cell plasticity and synaptic density. Meanwhile, senolytic drugs are being explored to restore intestinal stem cell function by clearing senescent niche cells, − although direct evidence for targeting senescent Paneth cells remains limited. However, limitations persist, such as current organoids lacking immune components critical for modeling senescence-associated inflammation, and reprogramming risks teratoma formation if pluripotency is incompletely controlled. − Innovations like microfluidic niche-mimetics and immune-cell-integrated organoids address these gaps and enable high-throughput screening of geroprotective compounds. − By bridging reductionist cell culture and complex in vivo environments, organoid technology accelerates the translation of niche-targeted therapies to combat stem cell exhaustion in aging tissues.

Age-Related Diseases: Mechanisms and Therapies

Neurodegeneration

The amyloid cascade hypothesis posits Aβ plaque accumulation as the central driver of AD (Figure A), but it faces mounting skepticism following decades of failed antiamyloid therapies. Although drugs like lecanemab modestly slow cognitive decline (∼27% over 18 months), their marginal efficacy underscores Aβ’s limited role in late-stage AD. − Emerging evidence implicates soluble tau oligomers, prefibrillar aggregates that disrupt synaptic function (Figure B), as more potent neurotoxins, correlating strongly with cognitive impairment in longitudinal studies. , Additionally, TDP-43 (Figure C) pathology is traditionally linked to amyotrophic lateral sclerosis and frontotemporal dementia but is also detected in AD brains, where it exacerbates neuronal loss and accelerates disease progression. − Beyond protein-centric models, dysregulated protein homeostasis (proteostasis) systems, including glymphatic clearance and ubiquitin-proteasome activity, are gaining traction as unifying mechanisms. , For example, glymphatic dysfunction in aging brains permits Aβ and tau accumulation, whereas vascular contributions (e.g., blood–brain barrier leaks) increase neurotoxicity. This shift urges multitarget approaches, i.e., tau immunotherapies (e.g., semorinemab) and TDP-43 antisense oligonucleotides in trials, to offer novel hope for patients resistant to amyloid-lowering therapies.

3.

Hierarchical mechanisms in neurodegenerative pathogenesis. Primary neurodegenerative agitators include soluble tau oligomers, which trigger AD pathology and induce oxidative stress, blood-brain barrier compromise, and neuroinflammation alongside fundamental presynaptic dysfunction. Known pathways encompass cholinergic hypothesis mechanisms involving (A) AChE dysregulation, Aβ accumulation, following (B) synaptic dysfunction, following hypersympathetic pathways that drive neuronal damage and cognitive decline, including (C) TDP-43 proteinopathy disrupting protein homeostasis and glymphatic clearance, SASP propagating neuroinflammation, and emerging senolytic mechanisms with potential age-reversal properties, establishing interconnected cascades that accelerate neurological decline.

Aged microglia are burdened by SASP factors (e.g., IL-6 and TNF-α), transition from neuroprotective sentinels to drivers of neuroinflammation and Aβ accumulation. , Next senescent microglia exhibit lysosomal deficiencies, impairing Aβ phagocytosis, whereas SASP cytokines activate astrocytes and recruit peripheral immune cells by creating a self-perpetuating inflammatory milieu. − Senolytics (e.g., dasatinib + quercetin) selectively eliminate senescent microglia, restore Aβ clearance, and reduce tau hyperphosphorylation in preclinical studies. ,, Early phase trials (e.g., NCT04685590) report reduced neuroinflammation markers in AD patients postdasatinib + quercetin treatment, although risks like off-target immune suppression persist. , Novel alternatives include microglia-targeted CAR-T cells and CSF1R inhibitors, which deplete senescent subsets without broad immunosuppression. However, concerns remain about disrupting homeostatic microglial functions, necessitating precision strategies. Thus, by addressing microglial senescence, these approaches could redefine AD treatment beyond the singular protein targets.

Cardiovascular Aging

Endothelial cell senescence is a pivotal driver of atherosclerosis, marked by diminished nitric oxide bioavailability and elevated ROS. Senescent endothelial cells lose their efficacy to regulate vasodilation and vascular tone due to eNOS uncoupling, which shifts nitric oxide synthesis to ROS production, exacerbating oxidative damage and inflammation. , This imbalance promotes adhesion molecule expression (e.g., VCAM-1), facilitates monocyte infiltration and foam cell formation in arterial walls. Additionally, SASP in aged endothelial cells releases IL-1α and MMP-9, destabilizing atherosclerotic plaques and increasing rupture risk. Recent work demonstrates that Navitoclax, a senolytic BCL-2 inhibitor, has demonstrated the ability to reduce senescent cell burden and SASP factors in aged nonhuman primates, contributing to improved markers of tissue health. Although the combination of navitoclax with mitochondrial ROS scavengers such as mitoTEMPO remains to be explored in primate models, its potential for synergistic enhancement of vascular function is promising. However, navitoclax-induced thrombocytopenia remains a significant dose-limiting toxicity that must be addressed in therapeutic applications. Novel alternatives, such as endothelial-specific CDK4/6 inhibitors, are now in development to minimize systemic toxicity, emphasizing the need for cell-type selective senotherapies. −

Age-related cardiac decline is fueled by defective autophagy associated with sustained mTORC1 activation, which impairs lysosomal degradation of damaged proteins and organelles. In aging cardiomyocytes, mTORC1 hyperactivity suppresses TFEB-mediated lysosomal biogenesis, resulting in the accumulation of misfolded proteins and dysfunctional mitochondria. , This disruption of proteostasis contributes to myocardial stiffness and impaired relaxation, which are features of age-related cardiac dysfunction. mTOR inhibition has demonstrated safety in clinical studies in older adults, and late-life rapamycin treatment improves cardiomyocyte relaxation kinetics and reduces myocardial stiffness in preclinical models. , In parallel, upstream activators of autophagy, such as spermidine and urolithin A, promote autophagy through mTOR-independent mechanisms. − highlighting complementary approaches to restore proteostasis in age-related cardiac decline.

Metabolic Disorders

Inflammaging is driven by IL-1β and NLRP3 inflammasome activation and is a key mediator of insulin resistance and type 2 diabetes (T2D). In aging adipose tissue (Figure ), mitochondrial dysfunction releases damage-associated molecular patterns (e.g., mitochondrial DNA, ceramides) that activate NLRP3 in macrophages, causing IL-1β release. This impairs insulin signaling through IRS-1 serine phosphorylation in hepatocytes and adipocytes, promoting hyperglycemia and lipid accumulation. − NLRP3 inhibitors such as MCC950 have been shown to reduce inflammation and improve insulin sensitivity in a mouse model of disease, whereas other studies indicate that NLRP3-driven islet inflammation may not contribute to metabolic dysfunction in db/db mice. , Notably, lifestyle interventions may exert anti-inflammatory effects as caloric restriction suppresses NLRP3 through ketone-mediated SIRT2 activation, and omega-3 fatty acids block IL-1β maturation by modulating macrophage plasticity. − Aging reshapes the gut microbiome toward pro-inflammatory taxa (e.g., Enterobacteriaceae), depleting butyrate producers like Faecalibacterium that maintain intestinal barrier integrity. , This dysbiosis increases circulating lipopolysaccharide, driving metabolic endotoxemia and adipose tissue inflammation. In elderly humans, low microbial diversity correlates with elevated TNF-α and insulin resistance, independent of diet. − Fecal microbiota transplantation from young donors restores microbial balance in aged mice, , and may reduce hepatic steatosis and improve glucose tolerance. Early human trials can reveal transient benefits as fecal microbiota diminishes within months unless paired with prebiotics like resistant starch, which selectively nourish transplanted commensals. Personalized approaches can further integrate metagenomic profiling to tailor fecal microbiota transplantation or phage therapies targeting pathobionts (e.g., Klebsiella). However, challenges persist, such as including donor-recipient compatibility and long-term ecological stability, yet microbiome modulation remains a frontier for reversing age-related metabolic decline.

4.

Age-related changes in adipose tissue contribute to inflammation and metabolic dysfunction. Healthy adipose tissue in youth transitions to a senescent state. This impairs mitochondrial function and reduces the metabolic balance, leading to lipid storage dysfunction and hypertrophic adipocyte formation. These alterations promote chronic inflammation through increased proinflammatory factors secretion and contribute to age-related metabolic disorders.

Translational Innovations

Next-Gen Senotherapeutics

First-generation senolytics, e.g., dasatinib plus quercetin (Figure ), pioneered the selective elimination of senescent cells by targeting pro-survival pathways (e.g., BCL-2, PI3K/AKT) and improved frailty in clinical trials and related studies, ,,, but limitations like poor oral bioavailability and off-target effects (e.g., dasatinib’s immunosuppression) restrict their utility. Next-gen candidates aim to enhance precision. For example, peptide-disrupting FOXO4-p53 interaction FOXO4-DRI selectively clears senescent cells by reinstating apoptosis and shows superior efficacy in fibrotic lung and renal aging models without harming healthy cells. , Similarly, HSP90 inhibitors (e.g., ganetespib) exploit senescent cells’ reliance on chaperone networks, inducing proteotoxic stress and death. Emerging solutions may include nanoparticle-based delivery systems, e.g., lipid-coated senolytics, which can improve tissue targeting in primate studies and reduce required doses by 70%. However, challenges persist in identifying universal senescence markers and avoiding unintended cell loss, but advances in single-cell proteomics can enable personalized senolytic regimens based on a patient’s senescent cell profile. Targeted senolytic and senomorphic therapies can reduce chronic inflammation and frailty, supporting individualized treatment plans guided by the senescent cell burden.

5.

Senolytic and senomorphic strategies for targeting cellular senescence. Senolytic therapies aim to eliminate senescent cells but are limited by poor bioavailability and unintended effects on nontarget cells. Senomorphic strategies aim to modulate the behavior of senescent cells using agents such as JAK-STAT inhibitors along with FOXO4 DRI and heat shock protein inhibitors. These required continuous administration. Slow-release systems and combination therapies are being investigated to enhance the effectiveness and minimize side effects.

Interestingly, senomorphics offer safer alternatives for chronic age-related conditions. To highlight, repurposed JAK/STAT inhibitors (e.g., ruxolitinib) block SASP-driven inflammation by intercepting IL-6/IL-8 signaling, showing promise in osteoarthritis. − Novel senomorphics target upstream SASP regulators, i.e., bromodomain inhibitors (e.g., JQ1), that disrupt BRD4-NF-κB crosstalk, attenuating cytokine release in aged fibroblasts, whereas mTOR inhibitors (e.g., everolimus) silence SASP via translational repression. , Unlike senolytics, senomorphics require continuous administration, raising compliance challenges. To address this, slow-release hydrogels are in development for intra-articular osteoarthritis treatment, sustaining drug activity for months. Critics caution that SASP suppression might hinder beneficial immune surveillance, necessitating context-specific dosing. Now, the field is shifting toward combinatorial approaches by pairing senomorphics with intermittent senolytics to maximize benefits while minimizing resistance and toxicity. −

Nutritional and Pharmacological Interventions

NAD⁺ precursors, e.g., nicotinamide riboside and nicotinamide mononucleotide, gained attention for their potential to counteract age-related NAD⁺ decline, though clinical outcomes remain contentious. − Nicotinamide riboside (commercialized as Niagen) has been shown to safely elevate NAD+ levels in middle-aged and older adults, supporting its potential as a nutritional intervention to counteract age-related declines in cellular metabolism and NAD+-dependent processes. Although some studies suggest that nicotinamide riboside may improve endothelial function via SIRT1-eNOS pathways, , precise effects on flow-mediated dilation and the mechanisms in humans remain under investigation. Safety concerns differ between NAD+ precursors: nicotinamide riboside has been generally well-tolerated in clinical studies, whereas nicotinamide was associated with effects on platelet function. − Critically, neither compound significantly impacts frailty or mortality in aged humans, underscoring the need for combinatorial approaches.

Fasting mimetics, such as spermidine and hydroxycitrate, replicate the benefits of caloric restriction without necessitating dietary changes. − In elderly humans, high dietary spermidine correlates with reduced cardiovascular mortality, although limited bioavailability of oral supplementation may restrict its therapeutic potential. − An ATP-citrate lyase inhibitor, hydroxycitrate, lowers cytosolic acetyl-CoA and promotes fatty acid oxidation and energy metabolism. , Innovations such as enteric-coated formulations and nanoparticle delivery systems may aim to enhance stability and tissue targeting. However, fasting mimetics face challenges as hydroxycitrate (Figure ) can cause gastrointestinal distress by delaying glucose absorption, whereas spermidine has been shown to ameliorate hypertension in preclinical models. , Emerging strategies can combine these agents with time-restricted eating to enhance the effects of intermittent fasting to optimize metabolic rejuvenation. NAD⁺ precursors and fasting mimetics offer practical, patient-accessible interventions to enhance metabolic health, potentially complementing lifestyle modifications in precision geroscience strategies.

6.

Mechanisms, limitations, and combinatorial potential of NAD⁺ precursors and fasting mimetics in aging intervention. NAD⁺ precursors counteract age-related NAD⁺ decline. Limited bioavailability and specific side effects restrict the effectiveness of these compounds and cause transient thrombocytopenia, whereas hydroxycitrate may lead to gastrointestinal discomfort. Combinatorial approaches with fasting mimetics may synergistically enhance the efficacy.

Gene and Cell Therapies

The advent of CRISPR-based gene-editing technologies revolutionized the field of aging research by offering precise tools to target the molecular drivers of senescence and age-related pathologies. For example, CRISPR-mediated targeting of p16INK4a enables selective ablation of these deleterious cells (Figure ), thereby ameliorating age-associated conditions, e.g., fibrosis and metabolic decline. − Next, SIRT6 overexpression is implicated in genomic stability and metabolic regulation and has been shown to delay aging phenotypes by improving DNA damage response and reducing oxidative stress. − These strategies focus on elucidating cellular and molecular mechanisms of aging in interventions that extend the health span. Recent preclinical studies highlight CRISPR efficacy in age-related disease models, including neurodegeneration − and cardiovascular disorders, , underscoring its translational promise. However, challenges, including delivery specificity, off-target effects, and ethical considerations, remain active areas of exploration. Developing a platform for critical analysis of these advancements may foster optimizing CRISPR-based therapies for clinical applications. By integration of novel insights from genetics, epigenetics, and systems biology, it is important to look into interdisciplinary approaches to translate laboratory breakthroughs into therapies to mitigate the burden of age-related diseases.

7.

CRISPR and CAR-T cell synergies for senescence targeting in age-related disease intervention. CRISPR-based gene editing enables precise targeting of key molecular drivers of cellular senescence to disrupt pro-aging pathways. CAR-T cell therapies can be engineered to selectively eliminate senescent cells through surface markers. These approaches mitigate chronic age-related pathologies, including fibrosis, metabolic dysfunction, and tissue degeneration.

Next, engineered CAR-T cell therapies were originally developed for cancer but are now being repurposed to target senescent cells, − marking a paradigm shift in aging research. This demonstrates the utility of CAR-T cells in eliminating senescence-associated markers, e.g., the urokinase-type plasminogen activator receptor, which is overexpressed in fibrotic tissues. In pulmonary and hepatic fibrosis preclinical models, urokinase-type plasminogen activator receptor-targeted CAR-T cells have shown remarkable efficacy in reducing senescent cell burden, restoring tissue homeostasis, and improving functional outcomes. − This approach capitalizes on immune system precision, offering a novel strategy to combat age-related chronic diseases without the systemic toxicity of conventional senolytics. This can explore how such therapies intersect with foundational aging mechanisms, e.g., immune dysregulation and chronic inflammation, driving conditions such as diabetes and neurodegenerative disorders. Furthermore, CAR-T therapies exemplify a commitment to bridging basic science and clinical innovation, as they build on decades of research into T-cell biology and senescence biomarkers. − Although challenges, e.g., antigen escape, cytokine release syndrome, and long-term persistence, require further study, CAR-T cells represent a frontier in personalized aging interventions (Table ). By featuring critical discussion on these developments, it is essential to catalyze progress in understanding how immune engineering can ensure that ethical, technical, and mechanistic dimensions of these therapies are rigorously examined in advancing translational strategies that address the global challenge of an aging population. CRISPR-based and CAR-T therapies provide precise tools to eliminate senescent cells or restore genomic stability, representing a frontier for clinical interventions against age-related tissue degeneration.

1. Key Interventions Targeting Age-Related Mechanisms.

intervention	context	outcomes	safety	mechanistic insight
dasatinib + quercetin	clinical trials; preclinical AD models	reduced neuroinflammation; improved frailty; eliminated senescent microglia	off-target effects; potential immune suppression	targets SASP-driven inflammation in senescent cells
rapamycin/mTOR inhibitors	preclinical animal studies; early human studies	extended lifespan in mice; improved vaccine response in humans; potential healthspan benefits	immunosuppression, glucose intolerance, impaired wound healing	inhibits mTOR-driven senescence and autophagy blockade
nicotinamide riboside	older adults	improved endothelial function; increased NAD+ levels	LDL elevation; transient thrombocytopenia; limited effect on frailty/mortality	supports SIRT1-eNOS signaling; vascular benefits noted
spermidine	observational studies in elderly humans	high intake associated with reduced cardiovascular mortality	poor oral bioavailability	fasting mimetic; supports autophagy and metabolic resilience
hydroxycitrate	elderly humans	promotes stress resistance and fatty acid oxidation	gastrointestinal discomfort; delays glucose absorption	fasting mimetic; ATP-citrate lyase inhibition
OSK epigenetic reprogramming	preclinical mice; human fibroblasts	reduced senescence markers; restored mitochondrial function; partially reversed epigenetic age	risk of incomplete dedifferentiation, genomic instability, and teratoma formation	Yamanaka factors (Oct4, Sox2, Klf4) used cyclically for safety
fecal microbiota transplantation	aged mice; human studies	restored microbial balance; improved glucose tolerance and hepatic function	microbiome stability; donor-recipient compatibility; transient effects	reverses dysbiosis and inflammaging
senomorphics (JAK/STAT inhibitors, bromodomain inhibitors, mTOR inhibitors)	older adults with systemic inflammation or osteoarthritis	reduced SASP-driven inflammation; improved joint function	continuous administration needed; may affect immune surveillance	modulates SASP without eliminating senescent cells
CAR-T/CRISPR interventions	preclinical aged mice; organoid models	eliminated senescent cells; restored tissue homeostasis	off-target effects; cytokine release syndrome; long-term persistence unknown	targets p16INK4a or urokinase-type plasminogen activator receptor in senescent cells

Controversies and Ethical Considerations

The use of rapamycin to extend lifespan has ignited vigorous debate within aging research (Figure ), reflecting a core focus on scrutinizing interventions with complex trade-offs. Although rapamycin robustly extends lifespan in model organisms linked to its inhibition of mTOR-driven senescence, inflammation, and metabolic dysfunction, its translation to humans remains challenging. − Clinical studies reveal that chronic mTOR suppression may induce immunosuppression, glucose intolerance, and impaired wound healing, effects that are inconsistent with its pro-longevity benefits observed in mice. − Thus, it is important to critically examine this paradox, emphasizing the need to reconcile mechanistic insights from animal models with human physiological realities. Strategies such as intermittent dosing or tissue-specific delivery aim to preserve rapamycin benefits and minimize adverse effects. For example, pulsatile (intermittent) administration in preclinical models reduces metabolic disruptions by maintaining antiaging effects. Furthermore, exploring how rapamycin’s pleiotropic actions, e.g., modulating autophagy, mitochondrial function, and proteostasis, intersect with age-related diseases like cancer and neurodegeneration. Thus, by fostering discussion on dose optimization, biomarker development, and patient stratification, it is crucial to highlight the importance of precision in aging interventions. This aligns with its mission to evaluate therapies not just through the lens of longevity but through their efficacy to enhance healthspan for ethical and practical considerations of translational geroscience.

8.

Strategies for optimizing rapamycin-based interventions to enhance healthspan during aging. Rapamycin demonstrates potential for extending lifespan and delaying aging. However, translation to humans is limited by adverse effects. Mitigation strategies include intermittent dosing or targeted delivery. Success can be redefined by prioritizing healthspan by improving functional aspects of aging over lifespan alone and continuing research into longevity mechanisms.

A growing critique in aging research challenges the field’s historical emphasis on lifespan extension without commensurate focus on healthspan. Many longevity interventions in animal models, e.g., genetic modifications or pharmacological treatments, extend maximal lifespan but fail to address age-related functional decline, which is evidenced by worsening frailty indices, cognitive deficits, or physiological resilience loss. − Thus, it is important to underscore the urgency of redefining success to prioritize health-span metrics, including mobility, organ function, and quality of life. For example, caloric restriction may extend the lifespan in diverse species but does not universally delay age-related pathologies in humans, highlighting disparities between laboratory outcomes and clinical relevance. Hence, it is important to explore for standardized, multidimensional healthspan assessments in preclinical research, integrating biomarkers like inflammaging markers or epigenetic clocks to better predict translational potential. − Additionally, it is crucial to spot interventions that uniquely enhance healthspan, e.g., exercise mimetics or senolytics, which improve functional capacity without necessarily altering lifespan. This may focus dedication to address age-related diseases, e.g., cardiovascular disorders and dementia, where delaying morbidity is as critical as extending survival. By interrogating the disconnect between longevity and healthspan, it is important to drive a paradigm shift toward interventions that prioritize quality, not just quantity, of aged life.

Cutting-Edge Tools and Technologies

The integration of multiomics approaches emerged as a transformative tool in aging research. By synthesizing data from diverse molecular layers, it is important to unravel complex aging biomarkers and pathways that evade single-omics analyses. Large-scale initiatives exemplify this paradigm, linking epigenetic clocks (e.g., DNA methylation patterns) with proteomic signatures of inflammation and metabolic dysregulation to predict biological age and intervention efficacy. − For example, multiomics profiling in caloric restriction studies identified novel mediators of longevity, e.g., NAD⁺ metabolism and mitochondrial adaptation, − which exposes heterogeneity in aging trajectories. It is important to emphasize how these integrative frameworks bridge gaps between cellular mechanisms and systemic aging, offering insights into diseases like AD, where Aβ pathology correlates with distinct metabolomic shifts. − Thus, addressing key challenges, including data harmonization across platforms and the need for computational tools to decode high-dimensional data sets, is still needed. By spotlighting studies that map omics-derived biomarkers to functional outcomes such as muscle resilience and cognitive decline, it is important to translate basic discoveries into clinically actionable strategies. This aligns with its focus on interdisciplinary innovation, as multiomics converges with systems biology to redefine aging as a dynamic, multidimensional process. Such advances not only refine personalized aging interventions but also establish benchmarks for evaluating emerging therapies, which is a cornerstone to advancing evidence-based geroscience.

Artificial intelligence and organ-on-a-chip technologies can reshape aging research, as in silico medicine generative networks are accelerating senolytic discovery by predicting compounds that selectively target senescent cells. , These tools address the bottleneck of traditional drug development, enabling rapid identification of candidates that modulate longevity pathways, such as mTOR or sirtuins. , Next, organ-on-a-chip systems represent an innovative advancement in aging by offering physiologically relevant platforms to study age-related tissue dysfunction and therapeutic interventions. These microfluidic devices replicate the structural and functional complexity of human organs, incorporating aged cellular microenvironments to model pathologies, e.g., neurodegeneration, vascular stiffening, and fibrosis. − For example, developing blood-brain barrier-on-a-chip systems may integrate aged endothelial cells, astrocytes, and pericytes to mimic the leaky barrier in AD and enable precise evaluation of drug permeability and neurotoxicity. − Hence, these systems can address limitations of traditional models, such as animal studies’ poor translational fidelity or static cell cultures’ lack of dynamic interactions. − by incorporating mechanical forces (e.g., shear stress), multicellular crosstalk, and biomarker secretion in real-time. Recent studies leveraging organ-on-a-chip platforms have uncovered age-specific drug toxicity profiles, e.g., increased sensitivity of aged cardiac tissue to chemotherapy, informing safer dosing strategies. , Thus, exploring innovations like “aging-in-a-dish” chips may accelerate cellular senescence through oxidative stress or pro-inflammatory cytokines to study disease progression and test senotherapeutics. ,, However, challenges persist, including standardizing aged tissue models across laboratories and scaling systems for high-throughput screening. Thus, it is important to emphasize the role of organ-on-a-chip technologies in bridging the preclinical findings and clinical outcomes gap for age-related diseases.

Critical Discussion

The field of aging research is marked by enduring theoretical debates, none more contentious than the conflict between the free radical theory of aging and the concept of mitohormesis. Hence, critically examining these paradigms underscores their implications for understanding age-related mechanisms and designing interventions. The free radical theory has long dominated geroscience, which is supported by correlations between ROS, mitochondrial dysfunction, and pathologies like neurodegeneration. However, mitohormesis challenges this view, proposing that low-level ROS act as signaling molecules to activate adaptive stress responses, enhancing longevity, which is observed in caloric restriction and exercise. , Thus, one can speculate that exploring antioxidant supplementation may accelerate aging in model organisms, undermining free radical theory. For example, nematodes with elevated ROS levels exhibit extended lifespans when mitohormetic pathways like SKN-1/Nrf2 are activated, suggesting context-dependent roles for oxidative stress. , Exploring how these conflicting theories inform current research, where free radical theory underpins approaches targeting oxidative damage (e.g., NAD⁺ boosters), , and mitohormesis drives interventions that modulate redox signaling (e.g., exercise mimetics). , Thus, emphasis is needed to reconcile these models through systems biology, integrating omics data to map the ROS dual roles in aging. This debate exemplifies the commitment to scrutinize initial assumptions, ensuring that emerging therapies are grounded in nuanced mechanistic understanding rather than oversimplified paradigms.

A critical gap in aging research is the inconsistent efficacy of interventions across sexes, exemplified by ketogenic diets extending the lifespan in male mice but not females. This disparity underscores the need to dissect sex-specific biological mechanisms. Hormonal differences, mainly the role of estrogen in modulating metabolic and oxidative stress pathways, may explain why females show muted responses to certain dietary interventions. , For example, estrogen enhances mitochondrial efficiency and antioxidant efficacy, potentially reducing ketogenic diet stress-induced benefits in females. , Thus, it is important to critique the historical exclusion of female subjects in preclinical studies, which obscures sex-dimorphic aging trajectories and limits translational relevance. Further, it is important to explore sex differences in mTOR signaling, immune senescence, and epigenetic aging, urging the adoption of dual-sex study designs. Furthermore, exploration of how gendered social determinants, e.g., access to healthcare or environmental stressors, interact with biological factors to shape aging outcomes. These insights align with the focus on equitable translation of aging, emphasizing that interventions must account for biological and societal variability to benefit diverse populations. By interrogating these gaps, one can drive a paradigm shift toward precision geroscience, ensuring that breakthroughs in longevity science do not perpetuate health inequities but instead deliver inclusive solutions to aging-related challenges.

Integrating mechanistic insights from telomere biology, epigenetic regulation, mitochondrial quality control, and stem cell niche dynamics with emerging translational tools, e.g., senotherapeutics, CRISPR-based interventions, artificial intelligence-driven drug discovery, and organ-on-a-chip platforms, can advance precision geroscience. Future research should prioritize biomarker-guided stratification, sex-specific analyses, and tissue-targeted delivery systems to modulate aging pathways while minimizing oncogenic and immunological risks. In parallel, the establishment of standardized healthspan end points and the harmonization of multiomics data with clinical phenotypes are essential to convert experimental geroprotective strategies into clinically actionable and equitable interventions for age-related multimorbidity.

Defining success in human aging studies requires end points to capture meaningful improvements in functional capacity, resilience, and disease burden, rather than merely lifespan extension. Practical clinical measures should include frailty indices, gait speed and mobility assessments, immune competence (e.g., vaccine responsiveness), cognitive performance, hospitalization frequency, and the onset or progression of multimorbidity. These outcomes reflect the multidimensional nature of healthspan, linking mechanistic interventions to real-world patient benefit. Biomarkers, e.g., epigenetic clocks, NAD⁺ levels, or inflammatory profiles, provide valuable mechanistic insight and early readouts of intervention efficacy, but should complement rather than replace functional end points. Thus, integrating robust clinical measures with biomarker data enables a comprehensive evaluation of geroprotective strategies, guiding translation from preclinical findings to interventions that improve resilience and quality of life in aging populations.

Conclusion

The unprecedented rise in global aging populations, coupled with the rising burden of age-related chronic diseases, underscores the urgent need to reframe aging as a modifiable risk factor rather than an inevitability. This review summarizes transformative insights from geroscience, emphasizing that targeting conserved aging mechanisms, e.g., genomic instability, epigenetic drift, mitochondrial dysfunction, and stem cell exhaustion, offers a novel shift from treating individual diseases to extending healthspan. By elucidating breakthroughs, e.g., senolytics, epigenetic reprogramming, and NAD⁺ boosters, we highlight their potential to decelerate aging processes and concurrently mitigate multiple pathologies, from neurodegeneration to cardiovascular decline. However, critical gaps persist. Translational challenges include inconsistent efficacy of interventions across species, safety concerns in partial reprogramming, and the ethical dilemma of prioritizing lifespan over healthspan. Further, sex-specific disparities in intervention outcomes and historical neglect of female models in preclinical research underscore the need for inclusive, precision-based approaches. Prospects should integrate multidimensional strategies, e.g., combining senotherapeutics with lifestyle interventions, advancing epigenetic clocks as dynamic biomarkers, and leveraging artificial intelligence-driven drug discovery and organ-on-a-chip systems to model aging complexities. Equally vital is implementing strategies to ensure that geroscience innovations are accessible and beneficial to diverse populations, minimizing the risk of exacerbating existing health disparities. By bridging mechanistic discoveries with clinical innovation, this perspective charts a path toward compressing morbidity and redefining aging as a malleable continuum of health and resilience.

Glossary

Abbreviations

Aβ

Amyloid beta

AChE

Acetylcholinesterase

AD

Alzheimer’s disease

ALT

Alternative lengthening of telomeres

AMPK

AMP-activated protein kinase

ATF5

Activating transcription factor 5

ATM

Ataxia-telangiectasia mutated

ATP

Adenosine triphosphate

ATR

ATM and Rad3-related

BCL-2

B-cell lymphoma 2

BLM

Bloom syndrome protein

BMP4

Bone morphogenetic protein 4

BRD4

Bromodomain-containing protein 4

CAR-T

Chimeric antigen receptor T cell

cGAS-STING

Cyclic GMP-AMP synthase–STING pathway

CDK4/6

Cyclin-dependent kinases 4 and 6

CRISPR

Clustered regularly interspaced short palindromic repeats

CSF1R

Colony-stimulating factor 1 receptor

DNA

Deoxyribonucleic acid

eNOS

Endothelial nitric oxide synthase

FANCM

Fanconi anemia complementation group M

FOXO4

Forkhead box O4

FOXO4-DRI

FOXO4 D-retro-inverso peptide

GrimAge

GrimAge epigenetic clock

H3K9me3

Histone H3 lysine 9 trimethylation

HSP90

Heat shock protein 90

IL-1α

Interleukin 1 alpha

IL-1β

Interleukin 1 beta

IL-6

Interleukin 6

IL-8

Interleukin 8

IRS-1

Insulin receptor substrate 1

JAK/STAT

Janus kinase–signal transducer and activator of transcription

JQ1

BET bromodomain inhibitor Jun Qi1

Klf4

Krüppel-like factor 4

Lgr5

Leucine-rich repeat-containing G-protein coupled receptor 5

MCC950

NLRP3 inflammasome inhibitor MCC950

MMP-9

Matrix metalloproteinase 9

mTOR

Mechanistic target of rapamycin

mTORC1

mTOR complex 1

NAD+

Nicotinamide adenine dinucleotide (oxidized form)

NF-κB

Nuclear factor kappa B

NLRP3

NLR family pyrin domain containing 3

Oct4

Octamer-binding transcription factor 4

OSK

Oct4, Sox2, Klf4

PI3K/AKT

Phosphoinositide 3-kinase/Protein kinase B

PINK1

PTEN-induced kinase 1

PML

Promyelocytic leukemia protein

POT1

Protection of telomeres 1

R-loops

RNA–DNA hybrid structures

RNA

Ribonucleic acid

ROS

Reactive oxygen species

SASP

Senescence-associated secretory phenotype

SIRT1

Sirtuin 1

SIRT2

Sirtuin 2

SIRT6

Sirtuin 6

Sox2

SRY-box transcription factor 2

SUV39H1

Suppressor of variegation 3–9 homologue 1

T2D

Type 2 diabetes

TAME

Targeting Aging with Metformin

TDP-43

TAR DNA-binding protein 43

TERRA

Telomeric repeat-containing RNA

TFEB

Transcription factor EB

TGF-β

Transforming growth factor beta

TNF-α

Tumor necrosis factor alpha

TRF2

Telomeric repeat-binding factor 2

VCAM-1

Vascular cell adhesion molecule 1

WRN

Werner syndrome protein

Wnt

Wingless-related integration site

Not applicable.

P.K.: Conceptualization, Review, First draft, Figures, and Revision. J.C.: Review, Figures, V.S.P.: Review, Edit, L.S.: Review, Edit, K.B.: First Draft, Review, Edit, Figures, and Revise.

This work did not receive any funding to declare.

Not applicable.

Not applicable.

The authors declare no competing financial interest.