Longevity Papers

Mitochondrial DNA (mtDNA) damage has been linked to age-related tissue decline, yet its impact on muscle stem cells (MuSCs) integrity remains unclear. Here, we used a dominant-negative variant of the mitochondrial helicase Twinkle (p.K320E) to induce mtDNA instability in C2C12 and MuSCs, and examined myogenic differentiation. In C2C12, mtDNA alterations impaired respiratory complex assembly, increased reactive oxygen species, and disrupted differentiation. Proteomic analyses of differentiated C2C12 revealed extensive remodeling of the mitochondrial proteome. In vivo, during muscle regeneration, MuSCs expressing K320E generated fibers showing mitochondrial dysfunction and elevated oxidative stress. Furthermore, when mtDNA instability was induced during early postnatal stages, mtDNA alterations were progressively transmitted to mature myofibers, resulting in persistent fiber remodeling of the skeletal muscle. Together, these findings identify mtDNA instability in muscle progenitors as a driver of skeletal muscle remodeling and reveal that even modest levels of mtDNA alterations are sufficient to compromise skeletal muscle function.

aging is a multifactorial process characterized by progressive loss of tissue homeostasis and regenerative capacity, with haematopoiesis being profoundly affected. Age-associated changes in hematopoietic stem cells (HSCs) include increased frequency but reduced function, impaired self-renewal, and myeloid bias, driven by both intrinsic defects and extrinsic cues from the bone marrow (BM) niche. While heterochronic BM transplantation (hBMT) has been used to distinguish donor- versus niche-driven mechanisms, most studies have focused on isolated readouts under simplified conditions.

Senescent cells, which are normally cleared by the immune system but accumulate with age, contribute to multiple disorders including metabolic dysfunction and impaired fitness. While immune checkpoint inhibitors have been well studied in cancer, the role of programmed cell death ligand 2 (PD-L2) in non-cancerous, age-associated cellular senescence remains unclear. We found that PD-L2 is upregulated in isolated senescent human cells and during aging, and senolytics can remove age-associated, highly PD-L2-expressing senescent cells. Old PD-L2 knockout mice accumulate fewer senescent cells than old wild-type mice, and their insulin sensitivity and grip strength are greater. Anti-PD-L2 therapy restored insulin sensitivity in aged wild-type mice. PD-L2 acts as an immune checkpoint on senescent cells, allowing them to evade immune clearance and promoting their persistence during aging. Targeting PD-L2 in senescent cells may be a strategy for alleviating the age-related dysfunction associated with cellular senescence.

The cGAS/STING pathway is a central innate immune signaling pathway responsive to cytosolic DNA. Chronic activation of this pathway promotes numerous age-related pathologies, but its impact on lifespan remains unknown. Here we engineer a cGAS knockout (KO) in the turquoise killifish Nothobranchius furzeri to assess effects on physiology and aging. In cultured fibroblasts, cGAS deficiency results in elevated DNA damage but reduces radiation-induced senescence and enhances cellular proliferation. In vivo, cGAS KO attenuates DNA damage-induced transcriptional responses in young fish, and blunts age-associated transcriptional changes in old fish, consistent with dampening of senescence and aging. Accordingly, old cGAS KO animals exhibit lower levels of senescence-associated β-galactosidase activity and higher levels of cell proliferation, without detectable differences in immune infiltration. Despite these attenuated aging signatures, lifespan is not extended. Together, these findings reveal that while cGAS loss alleviates senescence and age-related signatures, additional mechanisms constrain longevity.

Mitochondria integrate bioenergetics, redox signalling, calcium handling, biosynthesis, apoptosis, and stress responses. Their contribution to ageing depends less on any single pathway than on the ability to sustain these functions through continuous maintenance, remodelling, and inter-organelle communication. This review proposes mitochondrial homeodynamics as a systems-level framework for that ability, which rests not on static preservation but on three linked capacities. Maintenance safeguards mitochondrial genome, proteome, and membrane integrity. Adaptation adjusts metabolism and remodels network and cristae architecture to match changing demand. Recovery restores function and reserve after challenge. These capacities emerge from mitochondrial quality control, network and cristae remodelling, biogenesis, mitophagy, retrograde stress signalling, and inter-organelle communication. So defined, mitochondrial dysfunction becomes a measurable loss of capacity rather than a descriptive category. Ageing erodes these capacities in tissue- and context-specific ways, which reduces physiological reserve, slows recovery after stress, and amplifies sterile inflammation. The mechanisms underlying these capacities, the biomarkers that report them, and the interventions proposed to preserve them are evaluated in turn. Exercise provides the strongest human evidence for coordinated mitochondrial and functional adaptation, whereas evidence for energy restriction, NAD+ precursors, mitophagy-supporting compounds, and mitochondria-targeted agents remains heterogeneous and endpoint-specific. No mitochondrial intervention has been shown to slow ageing or extend lifespan in healthy humans, and movement of a biomarker towards a younger reference value does not establish rejuvenation. Progress will require dynamic measures of maintenance, adaptation, and recovery, obtained in defined tissues and interpreted alongside clinically meaningful outcomes.

SUMOylation is a reversible post-translational modification increasingly recognized for its role in coordinating cellular responses to metabolic stress during aging. Emerging evidence indicates that it functions beyond a conventional modification, representing an adaptive stress‑responsive regulatory network that integrates metabolic, oxidative, inflammatory, and proteotoxic signals. Rather than acting on isolated pathways, this network finely tunes mitochondrial function, proteostasis, genome maintenance, immune balance, and epigenetic regulation. Accumulating evidence indicates that SUMO-dependent regulation exhibits remarkable tissue specificity, supporting mitochondrial adaptation and contractile integrity in skeletal muscle, shaping lipid and glucose metabolism in the liver, modulating proteotoxic stress and neuronal resilience in the brain, and contributing to immune cell differentiation and chronic low-grade inflammation during aging. In this review, we summarize current mechanistic insights into SUMO signaling across aging-relevant tissues, with particular emphasis on its functional interplay with other post-translational modifications, including ubiquitination and acetylation. We discuss how SUMOylation operates as a shared regulatory layer while enabling context-dependent outcomes that underlie diverse aging phenotypes and age-related disorders. Finally, we evaluate emerging translational approaches-ranging from pharmacological modulation of SUMO enzymes to lifestyle interventions such as caloric restriction and exercise-that highlight both the opportunities and challenges of targeting SUMO-regulated stress responses in aging. Together, this synthesis provides a framework for understanding how SUMOylation links metabolic stress to tissue-specific aging trajectories and therapeutic potential.

Skeletal muscle stem cells (MuSC) are the guardians of muscle regeneration, sustaining tissue integrity through a delicate balance of quiescence, activation, and lineage commitment. While numerous molecular cues have been implicated in regulating these processes, the influence of androgen receptor (AR) signaling, an essential hormonal pathway for male muscle physiology, has remained largely unexplored. Here, we show that AR expression defines quiescent MuSC and acts as a safeguard of their dormancy. Integrated multiomic analyses reveal a redistribution of AR binding from quiescence-maintenance loci to regulatory elements driving activation and metabolic reprogramming during repair. Loss of AR in young adult mice disrupts this balance, precipitating premature cell-cycle entry, skewed division modalities, depletion of the stem cell reservoir, and destabilization of the niche. These defects converge with hallmarks of aging-associated androgen decline, while androgen supplementation restores regenerative competence. Together, our findings establish AR signaling as a pivotal determinant of MuSC fate and a cornerstone of skeletal muscle homeostasis.

Aging skin is characterized by wrinkles, loss of elasticity, and impaired barrier function, largely driven by alterations in dermal fibroblasts and extracellular matrix remodeling. Chronic, age-related inflammation, called inflammaging, is a central activity underlying these changes. Immunoglobulin G (IgG) has recently been shown to accumulate in multiple organs with aging, where it activates macrophages to promote tissue inflammation. However, whether IgG contributes to skin aging remains unknown. Here, using mouse and human tissues we show that IgG accumulates in the dermis with age and promotes dermal inflammation and atrophy. Moreover, experimental IgG administration to young mice induced chemokine expression, facilitating infiltration of skin tissue by macrophages and T cells. These findings support a model whereby IgG activates macrophages to produce chemokines and interleukin-12, enhancing interferon-γ production by T cells and suppressing collagen synthesis in fibroblasts. These findings strongly suggest that IgG drives cutaneous skin inflammation and skin aging via crosstalk between immune cells and fibroblasts, and that targeting IgG accumulation or downstream signaling may delay skin aging and extend tissue healthspan.

The evolutionary biology of aging is fundamental to understanding the mechanisms of aging and how to develop anti-aging treatments. Thus far most evolutionary theory concerns the genetics of aging with limited physiological integration. Here we present an intuitive evolutionary framework built on how physiology is regulated and how this regulation itself ages. Life has evolved to secure reproduction and avoid system failure in early life, and it is the regulation that evolves in response to those early life selection pressures that we suggest leads to the emergence of aging. The costs of dysregulation of physiology are not symmetrical, for example, they are not the same for over- and under-activation. As a consequence, asymmetry in the regulation of physiology will evolve. When asymmetrical regulatory systems break during aging, they cause physiological function to drift toward the physiological range where costs of dysregulation are lowest, rendering aging directional. Our model explains many puzzling aspects of the biology of aging. These include why aging appears (but is not) programmed, why aging is gradual yet heterogeneous, why cellular and hormonal signaling are closely related to aging, the compensation law of mortality, why trade-offs between reproduction and aging remain elusive, why longer-lived organisms show more signs of aging during their natural lifespans, and why longer-lived organisms can be less responsive to anti-aging treatments. We provide predictions of our theory that are empirically testable. By incorporating physiological regulation into evolutionary models of aging, we provide a novel perspective to guide research in this growing field.

Aging progressively challenges neuronal proteostasis, redox homeostasis, and metabolism, yet the molecular changes that precede functional decline remain poorly understood. Endoplasmic reticulum oxidoreductin 1 (ERO1), a key regulator of oxidative protein folding, links endoplasmic reticulum (ER) proteostasis with cellular redox balance and is elevated in aging and neurodegenerative contexts. Here, we investigated how neuronal ERO1L elevation reshapes cellular homeostasis before overt dysfunction in Drosophila melanogaster. Endogenous ERO1L expression increased with age, and neuronal ERO1L elevation shortened lifespan and caused progressive locomotor decline. This effect was strongly cell-type dependent, as ERO1L elevation in glia, muscle, or fat body did not produce a comparable survival phenotype. At day 5 post-eclosion, locomotor performance remained preserved and major brain reactive-oxygen-species (ROS) accumulation was not yet detectable, defining a pre-symptomatic stage. Multi-omic profiling at this stage revealed selective remodelling of ER proteostasis, redox defence, and mitochondrial-energy pathways, together with changes in central-carbon, nitrogen, and purine metabolism. In contrast to these broadly adaptive responses, chromatin- and RNA-homeostasis-associated proteins were selectively reduced, accompanied by decreased HP1, dFmr1, and Piwi expression and increased transposable-element transcripts. Thus, neuronal ERO1L elevation establishes a pre-symptomatic state in which proteostatic and metabolic adaptation coexists with early vulnerability of nuclear and RNA-homeostasis pathways, preceding overt oxidative stress and behavioural decline. These findings provide an in vivo framework to investigate how age-associated ERO1L elevation may progressively reduce neuronal resilience during brain aging.

Drugs for aging-related diseases may modulate aging itself, but standard clinical trial designs cannot detect such effects. Aging clocks could close this gap, but epigenetic models often yield inconsistent, hard-to-interpret results. In contrast, proteomic clocks, by tracking the immediate effectors of biological change, may excel in providing aging biomarkers or mechanistic insight. Here we compare six proteomic clocks (ProtAge, OrganAge

Aging and type 2 diabetes (T2D) are increasingly recognized as interconnected biological processes that share core pathogenic mechanisms, including cellular senescence, mitochondrial dysfunction, chronic low-grade inflammation, impaired autophagy, stem cell exhaustion, dysregulated nutrient sensing, and gut microbiota imbalance. Chronic hyperglycemia and insulin resistance accelerate tissue degeneration across multiple organ systems, thereby establishing T2D as a clinically relevant model of accelerated biological aging. In this context, anti-diabetic medications have attracted growing interest not only as glycemic control agents, but also for their potential to modulate aging biology and delay age-related functional decline. Here, we review the emerging evidence supporting the senotherapeutic properties of metformin, sodium-glucose cotransporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), alpha-glucosidase inhibitors (AGIs), sulfonylureas (SUs), thiazolidinediones (TZDs), and insulin. These agents have been reported to influence key aging-related pathways, including AMPK, mTOR, SIRT1, NF-κB, ROS/c-JNK, and insulin/IGF-1 signaling, and to exert beneficial effects on cellular senescence, inflammaging, mitochondrial homeostasis, proteostasis, immunosenescence, autophagy, and gut microbiota composition. Despite strong preclinical support, translational relevance remains uncertain due to model heterogeneity, limited randomized clinical evidence, and insufficient long-term follow-up. Clarifying tissue specificity, timing, dose, and patient selection will be essential for determining whether anti-diabetic agents can be safely repurposed as gerotherapeutics.