Longevity Papers

Ageing is associated with loss of skeletal muscle mass and strength (sarcopenia) and disrupted redox homeostasis. Redox signalling is essential for muscle adaptation, yet the mechanisms by which ageing disrupts cysteine-based regulation are poorly defined. The drivers of site-specific reactivity and signalling specificity in aged muscle remain unknown. Here, we interrogated the OxiMouse dataset to map age-related cysteine oxidation in skeletal muscle and, using AI, simulate oxidative modifications at key cysteine residues to predict structural and functional consequences for specific proteins. Ageing was found to remodel the redox landscape through selective oxidation of discrete cysteine residues, in a site-specific manner, even within the same protein. These findings support that ageing drives pathway-targeted modulation of protein function rather than a uniform, global oxidative shift. Moreover, age-related cysteine oxidation is not randomly distributed but appears to target interconnected protein networks involved in mitochondrial metabolic pathways, muscle function and proteostasis, indicating a coordinated remodelling in redox signalling as a hallmark of skeletal muscle ageing. To connect proteomic signatures to mechanisms, AlphaFold3 was used to simulate progressive cysteine oxidation and predict structural outcomes. Protein docking simulations were then performed using HADDOCK. This approach was applied to prioritise functionally important cysteines identified in the dataset. These results suggest that skeletal muscle ageing drives selective rewiring of physiologically relevant cysteine-based redox signalling networks. By integrating redox proteomics with AI-based structural simulation, this study provides a framework to prioritise key oxidation-sensitive cysteines, including within the 26S proteasome, as potential mechanistic nodes and intervention targets for sarcopenia.

Quantifying differences in aging among individuals of the same chronological age could provide a direct measure of biological aging. However, existing methods often estimate biological age by predicting chronological age and treat such individual differences as prediction errors. We developed InferAging, a framework that estimates biological age by explicitly modeling individual deviations from chronological age. In progeroid zebrafish (klotho mutant; kl-/-), InferAging identified accelerated and delayed agers within the same chronological age group. A non-invasive variant using behavioral and morphological snapshots reproduced the transcriptome-integrated estimates without molecular input or lifelong tracking. The inferred aging state was associated with metabolic decline, intestinal barrier dysfunction, inflammation, and mucosal immune abnormalities beyond chronological age. These results demonstrate that non-invasive phenotypes can reveal molecularly supported individual aging states.

Cellular senescence, a complex biological process characterized by irreversible cell cycle arrest and the senescence-associated secretory phenotype, has emerged as a critical target for therapeutic development for age-related diseases. Ferroptosis, an iron-dependent regulated cell death pathway driven by the accumulation of lipid peroxidation in cell membranes, has been implicated in age-related disorders. This study investigated the relationship between cellular senescence and ferroptosis. Using human fetal lung WI-38 fibroblasts induced to senesce via replicative exhaustion, we report a novel role for acid ceramidase (ACase), which breaks down ceramides into sphingosine and free fatty acids, in regulating the sensitivity of senescent cells to RSL3-induced lipid peroxidation and ferroptosis through the modulation of polyunsaturated fatty acid composition of membrane phospholipids. Furthermore, we demonstrate a cell non-autonomous paracrine sensitization of non-senescent cells to ferroptosis by senescent cells. Together, these findings unveil ACase as a novel regulator of the ferroptosis pathway and open promising therapeutic avenues for targeting senescence-linked disorders and advancing healthy aging strategies.

Chronic inflammation, oxidative stress, and metabolic dysfunction are central drivers of biological aging. Polyphenolics from

Anemia, the most prevalent hematologic disorder in older adults, imposes a significant burden of cardiovascular events, cognitive decline, and mortality. However, the mechanisms underlying aging-related anemia, especially epigenetic dysregulation in hematopoietic stem and progenitor cells (HSPCs), remain incompletely understood. Although the gut microbiota is critical for hematopoiesis, its specific contribution to aging-related erythropoiesis impairment remains unclear. Here, we reveal that aging markedly activates phenylalanine metabolism and elevates plasma phenylacetic acid (PAA) levels in both humans and mice. We identify Odoribacter splanchnicus (O.splanchnicus) as a key gut symbiont whose abundance is significantly increased in aged mice and which directly drives PAA production from phenylalanine via the oxoacid:ferredoxin oxidoreductase (OFOR) superfamily encoded by porA,nifJ, and iorA/iorB. Rifaximin treatment selectively reduces O.splanchnicus and plasma PAA, thereby alleviating aging-related anemia. Mechanistically, PAA promotes a novel post-translational modification (PTMs) termed histone lysine phenylacetylation (Kpa) through the acetyltransferases HBO1. Elevated histone Kpa increases chromatin accessibility at the GATA2 promoter, disrupts the GATA switch, and blocks erythroid differentiation of HSPCs. In vivo, supplementation with sodium phenylacetate (NaPA) exacerbates anemia in microbiota-depleted mice, whereas the HBO1 inhibitor WM-3835 restores erythropoiesis by reversing histone Kpa and normalizing the GATA switch. Furthermore, dietary phenylalanine restriction lowers circulating PAA and effectively ameliorates aging-related anemia in both naturally aged mice and O.splanchnicus-colonized mice. These findings provide the first evidence that gut microbiota-derived PAA plays a critical role in the development of aging-related erythropoiesis impairment and offer multiple translatable strategies for treating this condition.

Regeneration of skeletal muscle preserves muscle mass and function, which decline with age. Here, we sought to identify long noncoding (lnc)RNAs involved in skeletal muscle myogenesis and potentially relevant to muscle aging. Cross-sectional analysis of skeletal muscle transcriptomes from healthy 22-through 89-year-old individuals revealed lncRNA LANCL1-AS1 among the top declining transcripts. Conversely, LANCL1-AS1 increased robustly during skeletal myogenesis and promoted myogenic differentiation in culture. Affinity pulldown by ChIRP followed by mass spectrometry revealed that LANCL1-AS1 associated with the mitochondrial protein LRPPRC, enhancing the formation of the chaperone complex LRPPRC-SLIRP, which maintains longer poly(A) tails of mitochondrial (mt-)mRNAs and stabilizes mt-mRNAs. Importantly, while myoblasts from old rhesus monkey muscle expressed lower levels of LANCL1-AS1 and mt-mRNAs, and displayed lower mitochondrial activity than young monkey myoblasts, overexpressing LANCL1-AS1 in old myoblasts restored mitochondrial activity and myogenesis. We propose that the age-associated reduction in LANCL1-AS1 contributes to impaired mitochondrial function and reduced myogenic capacity in aging skeletal muscle.

Proteostasis declines with lung aging, while the role of the Unfolded Protein Response (UPR) in lung aging and age-associated pulmonary diseases remains understudied. We investigated how deficiency in the UPR sensor ATF6 affects physiological and smoke exposure-accelerated lung aging. ATF6 -deficient mice exhibited accelerated alveolar simplification, a sign of lung parenchymal aging, which was exacerbated by smoking. Nevertheless, small airway vascular fibrotic remodeling, a prominent smoking induced pathology, was not evident in smoke-exposed ATF6 -deficient mice. Mechanistically, these divergent phenotypes arose from cell-type-specific ATF6 programs. In alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of the lung parenchyma, ATF6 maintained mitochondrial bioenergetics and sustained efficient re-differentiation into alveolar epithelial type 1 cells (AEC1s). In lung pericytes, ATF6 promoted extravasation, re-differentiation into myofibroblast-like cells, and production of collagens 1 and 3. These findings identify ATF6 as a cell-type-specific regulator of differentiation programs during lung aging and highlight the need to study ATF6 under defined physiological and pathological contexts before therapeutically targeting this pathway.

Geroscience clinical trials need biomarker surrogate endpoints for healthspan. Leading candidates are omics-based composites developed from machine learning analysis of aging phenotypes including calendar age, survival, functional capacity, and Pace of Aging. Existing Pace of Aging biomarkers were developed in the Dunedin Longitudinal Study, limiting inference about strengths/weaknesses of the method as distinct from the Study, a unique single-year birth cohort followed through midlife with near-perfect retention and uniform measurement of multi-organ-system function across two decades of follow-up. We adapted our Pace of Aging method for mixed-age cohorts with variable follow-up of organ-function measures and applied it to develop a novel DNA methylation biomarker of Pace of Aging in data from the Framingham Heart Study Offspring Cohort, FraminghamPACE. Validation analyses across four independent cohorts and one clinical trial establish advantages for the Pace of Aging method in developing biomarkers that are both predictive of healthspan and responsive to geroprotective intervention.

compromises hematopoietic stem cell (HSC) maintenance, contributing to an extrinsic HSC aging phenotype. Although niche-derived Notch signaling is essential for hematopoietic regeneration following myelosuppressive injury, the upstream epigenetic mechanisms that regulate this stress-responsive signaling remain poorly understood. Here, we identify the chromatin remodeler BRM (SMARCA2) as a critical regulator of the BM sinusoidal niche that preserves vascular integrity and hematopoietic regeneration. Using reciprocal BM transplantation, we demonstrate that a Brm-deficient microenvironment impairs HSC repopulating capacity and imposes an aging-like myeloid bias characterized by expansion of granulocyte-monocyte progenitors. Following 5-fluorouracil (5-FU)-induced myelosuppression, BrmKO mice exhibit defective sinusoidal regeneration accompanied by endothelial degeneration. Mechanistically, BRM deficiency attenuates endothelial Notch signaling by impairing stress-induced Notch2 expression in sinusoidal endothelial cells (SECs), while simultaneously reducing Jag2 ligand pool through persistent depletion of SECs and impaired stress-induced expansion of Jag2-producing LepR-positive stromal cells. These alterations attenuate endothelial Notch signaling, resulting in defective sinusoidal regeneration, loss of mesenchymal niche support, and progressive displacement of HSCs from the sinusoidal vasculature. Notably, Brm expression is physiologically reduced in aged wild-type SECs and LepR-positive stromal cells. Collectively, our findings identify BRM as a key epigenetic regulator of bone marrow niche integrity and suggest that age-associated BRM decline contributes to niche dysfunction and hematopoietic aging.

Heat shock transcription factor HSF1 maintains proteome integrity via the induction of heat shock proteins. Here, we provide a comprehensive overview on the structure, function and regulation of HSF1 in multiple organisms. We summarize the aging-associated changes of HSF1 function, the reduced inducibility of the heat shock response, leading to a model of age-related stochastic HSF1 activity decline. Besides, we review basal, non-canonic HSF1 functions through regulating distinct transcriptional outputs which support development, reproduction, tissue proteostasis maintenance, growth- and cancer-related anabolic processes. Based on major observations in the nematode C. elegans demonstrating differential regulation of these outputs, we propose a novel mechanistic framework that draws on the life history-coupled programmed remodeling of its transcriptional function at the onset of reproduction. The HSF1 output selection model accounts for the coexistence of diminished stress inducibility with sustained or increased basal HSF1 activity and explains why broad HSF1 activation may benefit proteotoxic diseases but pose risks in cancer-prone conditions. Experimental approaches leveraging age- and tissue-specific transcriptomic, chromatin, and post-translational analyses are outlined, emphasizing selective restoration of protective HSF1 outputs over indiscriminate activation.

The pace of aging can be delayed by mutations, dietary manipulations, and drugs, yet the metabolic mechanisms underlying longevity interventions remain poorly understood. Here we present a multi-tissue metabolomic analysis of male UM-HET3 mice treated from 4 to 12 months of age with five validated longevity interventions: rapamycin, acarbose, 17-estradiol, canagliflozin, or caloric restriction. Using a feature-stabilized XGBoost pipeline applied to seven tissues, we show that metabolomic profiles can identify treated mice as likely recipients of a lifespan-extending intervention well before survival differences emerge. A leave-one-intervention-out procedure confirmed that models trained on any four interventions successfully classified mice from a fifth, unseen intervention, implying shared metabolic alterations across mechanistically distinct treatments. The most influential metabolites -- defined as the minimum set explaining 50% of cumulative model gain -- differed substantially across tissues. Only ergothioneine, a dietary antioxidant, ranked highly in more than two tissues: it was elevated by all five interventions in plasma and brain, and by four of five in muscle. Enrichment analyses further identified coordinated remodeling of lipid classes in plasma, perigonadal fat, and kidney. These findings reveal tissue-specific metabolic reprogramming shared across mechanistically distinct longevity interventions and, pending validation against interventions that do not extend lifespan, suggest a path toward metabolomic screening of candidate anti-aging drugs.

Rapamycin extends lifespan across species, yet its cell-type-specific benefits and vulnerabilities remain unclear at whole-organism scale. Here, we present the Rapamycin Fly Cell Atlas (Rapa-FCA), a whole-organism single-nucleus transcriptomic atlas of Drosophila spanning both sexes, multiple ages, 18 cell classes, and 181 cell types. Rapamycin elicited a highly heterogeneous response, with prominent effects in reproductive, digestive, and neuromuscular systems and modest responses in most neuronal populations. Across diverse tissues, we identified a rapamycin-sensitive Convergent Aging Trajectory (CAT), marked by Fkbp12 enrichment and mTORC1-linked metabolic programs, including glycolysis and lipid synthesis. CAT-high nuclei accumulated with age and were preferentially reduced by rapamycin, especially in females, consistent with stronger female lifespan extension. By integrating CAT abundance, aging-clock predictions, and nucleus-ratio changes, we mapped sex- and cell-type-specific geroprotection effects of rapamycin. Together, the Rapa-FCA provides an organism-wide framework for resolving how rapamycin reshapes cellular aging across sex, tissue, and cellular state.

A central challenge in computational geroscience is to distinguish molecular quantities that predict mortality from those that causally drive it. Epigenetic clocks and aging biomarkers are increasingly used as if they were that mechanism, yet this is rarely tested directly. This distinction also bears on competing theories of aging: damage/reliability (A), hyperfunction/mTOR-IIS (B-1), and information loss (B-2). Although individual aging proteins have been tested piecemeal, no study has asked, in one framework, what fraction of mortality is measurable, whether it is causal, and whether it is reversible. Using only public, de-identified data, we evaluate this three ways. First, a Markov generator-matrix model of hallmark-load dynamics with death as an absorbing state, fitted by Bayesian inference through a joint biomarker-and-mortality likelihood to NHANES with linked mortality (n=23,844) and replicated in the Health and Retirement Study (HRS), decomposes Gompertz acceleration into visible (measured-biomarker-driven) and latent components. Second, a positive-control-calibrated, two-platform cis-pQTL Mendelian-randomization and colocalization design (UKB-PPP, deCODE) against parental-lifespan GWAS tests whether the latent's measurable components are causal. Third, a clock battery (Horvath, chronological; DamAge, causality-enriched damage) tests reversibility in cellular reprogramming. Within the model, ~92% of Gompertz acceleration is assigned to a latent component not captured by measured blood-biomarker axes (NHANES 92.5%, HRS 91.6%); the latent is partly encoded in DNA-methylation signatures but not transcription. The known causal proteins are detected (LPA p=9x10-12; IL6R p=2.8x10-5), yet the latent's components, across inflammatory, renal and growth-signalling (IGFBP3, IGF-1) axes, are null and do not colocalize on either platform. Reprogramming reverses the chronological clock (-11 to -22 yr) but not the causality-enriched damage clock. The model-inferred mortality-driving component is largely latent to accessible biomarkers; its measurable molecular proxies show no supported causal effect where the design detects known causes; and the causality-enriched damage-clock signal is resistant to partial reprogramming.

The neuropathology of Parkinsons disease is characterized by -synuclein (-syn) aggregation and dopaminergic (DAergic) neurodegeneration. While neuronal loss in C. elegans -syn-induced neurodegeneration models is temporally age-dependent, prior research indicates it is uncoupled from the organismal aging process. Here we examined transgenic C. elegans expressing human A53T -syn in DAergic neurons to determine the impact of localized DA metabolism on both neurodegeneration and organismal lifespan. Increasing endogenous DA levels through overexpression of tyrosine hydroxylase (CAT-2) exacerbated A53T-induced DAergic degeneration, whereas DA depletion via {Delta}cat-2 mutation rescued neuronal survival. By mutating a DA-interaction motif within -syn, neurodegeneration was rendered insensitive to DA manipulation, thus confirming a structural basis for in vivo toxicity. We identified a DA--syn interaction that acts as a common upstream bridge whereby localized stress induces physiological responses in C. elegans. Genetically, this biochemical interaction acts as a pleiotropic trigger driving two compartmentalized responses: localized DAergic neurodegeneration via oxidative stress, and organism-wide, TFEB/hlh-30-dependent proteostatic remodeling that extends lifespan. Modulating autophagy, without exacerbating DA-mediated oxidative stress, represents a promising strategy to preserve adaptive systemic remodeling while limiting targeted neuronal damage.

The incidence of early-onset colorectal cancer (CRC) has risen sharply in recent decades1, yet the biological basis underlying the distinct behavior of tumors arising in young versus aged tissues remains poorly understood. Here we show that aging reprograms the epigenetic landscape of the colon, restricting colon tumor growth through stable silencing of developmental and fetal gene programs. We find that colon tumors arising in aged mice are intrinsically less proliferative than those arising in young animals. Multi-omic profiling of normal colon and colon tumors reveals that aging drives DNA hypermethylation, loss of Polycomb-associated chromatin states, and reduced chromatin accessibility at a defined set of developmental genes that are bivalent (marked by both H3K27me3 and H3K4 methylation), transcriptionally active in colon tumors from young animals and repressed in both tumors and normal tissue from old animals. Among the genes most strongly repressed in old animals is Tacstd2 (Trop2), a regulator of fetal intestinal programs and epithelial stemness. Pharmacologic inhibition of DNA methylation reactivates the aging-silenced gene network in organoids from old animals, whereas genetic disruption of Tacstd2 suppresses growth and developmental transcriptional programs in young tumor organoids. TACSTD2, fetal gene signatures, and the aging-associated bivalent gene program are likewise repressed in late-onset vs. early-onset human colorectal cancers. Collectively, these findings identify age-associated epigenetic silencing of developmental gene programs as a causal mechanism that constrains colorectal tumor growth and provide a mechanistic framework for understanding the distinct biology of early-onset colorectal cancer.

Age-related thymic involution is a central feature of immunosenescence and intersects with multiple "hallmarks of aging", including genomic instability, telomere attrition, mitochondrial dysfunction, and chronic inflammation. The decline in thymic epithelial integrity and FOXN1-driven thymopoiesis reduces naïve T-cell output, contracts TCR repertoire diversity, and perturbs central tolerance, contributing to increased susceptibility to infection, cancer, and autoimmunity. These changes occur alongside broader immune-aging phenomena such as inflammaging and frailty and are reflected in poorer vaccine responses and altered outcomes to novel pathogens such as SARS-CoV‑2. This review integrates mechanistic, preclinical, and human data to reassess the adult thymus as a therapeutic target. Higher-confidence domains for thymic restoration include cancer immunosurveillance, infectious disease vulnerability, vaccine responsiveness, and post-treatment immune reconstitution, supported by modeling of age-related disease incidence, transplant and HIV cohorts, and new observational links between radiographic thymic health, mortality, and immunotherapy outcomes. High-plausibility but less directly validated domains include autoimmunity, chronic herpesvirus control, HIV immunological non-responders, and post-acute infection syndromes such as long COVID, which share convergent patterns of T-cell dysfunction and persistent immune activation. The translational landscape spans hormonal and somatotropic modulation (sex steroid ablation, growth hormone/ghrelin), cytokine and growth-factor strategies (IL‑7, IL‑22, KGF/BMP4, FGF21), cell- and tissue-engineering approaches leveraging thymic epithelial stem cells and FOXN1-reprogrammed stromal cells, and gene-therapy concepts such as intrathymic AAV delivery of FOXN1, AIRE, chemokines, and stromal-support pathways. Collectively, these data support the biological plausibility of adult thymus restoration but highlight that robust, domain-specific clinical benefits have not yet been demonstrated in controlled trials. Future work should prioritize harmonized structural and functional biomarkers, domain-focused interventional studies in high-risk populations, and combined strategies that situate thymus-directed interventions within broader efforts to modify immune and organismal aging.

Cellular senescence has emerged as a central mechanism driving cutaneous aging, impaired regeneration, and numerous dermatologic pathologies. Initially evolved as a protective mechanism to prevent malignant transformation and facilitate wound repair, senescence becomes maladaptive when senescent cells persist. Senescent keratinocytes, fibroblasts, and melanocytes can secrete pro-inflammatory mediators and other factors, collectively termed the senescence-associated secretory phenotype (SASP), which may degrade extracellular matrix components, disrupt pigmentary balance, and impair barrier function. Senescent cells are resistant to conditions that cause death of non-senescent cells and are generally removed by the immune system. Persisting senescent cells can become increasingly pro-inflammatory and fibrotic, perhaps due to accumulating DNA damage within these cells. Two primary geroscience-based therapeutic paradigms (gerotherapeutics) have been proposed: senolytics, which selectively eliminate senescent cells, and senomorphics, which modulate or suppress SASP activity without inducing senescent cell death. In dermatology, these approaches are particularly relevant given skin's accessibility, visible aging markers, and ability to serve as a translational platform for systemic gerotherapeutic interventions. Interfering with the development of senescent cells, for example by interfering with such regulators of senescent cell formation as p16, retinoblastoma protein (pRB), p53, or p21, can be detrimental due to the protective roles of transient senescence in wound healing and cancer suppression. However, senolytics, which do not prevent senescent cells from developing but rather act by clearing already formed persisting and tissue-damaging senescent cells, offer the potential to delay, prevent, alleviate, or treat aged or fibrotic skin. Because of the days to weeks for senescent cells to form fully and their inability to divide, senolytics can be administered intermittently, for example for brief intervals every 2 weeks or once a month. Senomorphics, conversely, can modulate the detrimental effects of the SASP and generally need to be administered continuously or more frequently than senolytics. Some agents are both senolytic and senomorphic. This review considers the mechanistic underpinnings of senescence in skin, the evidence for both therapeutic approaches, and the future directions for integrating senotherapeutics into regenerative and aesthetic dermatology. Advances in cutaneous biomarkers, topical delivery systems, and AI-assisted patient stratification are expected to accelerate translation into clinical practice.

Mitochondrial dysfunction induces metabolic dysregulation in immune cells that is etiologically associated with age-related brain disorders. However, how dysfunctional mitochondria in microglia-the brain-resident immune cells-initially affect neurological function remains incompletely understood. Here, we demonstrate that dysfunctional mitochondria in microglia, induced by the conditional knockout of mitochondrial transcription factor A, act as triggers of metabolic dysregulation, cognitive aging, and neurodegeneration in adult mice. Notably, this metabolic disturbance induces a microglial transition to states associated with neuroinflammatory activation and neurodegenerative disease, thereby triggering multiple layers of pathological cascade reactions among other brain cell types and shaping a neuroinflammaging state at single-cell resolution. Mechanistically, mitochondrial dysfunction activates the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which mediates immune sensing of cytosolic DNA in microglia and contributes to inflammaging. We further present evidence that combined treatment aimed at restoring metabolic homeostasis and inhibiting neuroinflammatory cGAS-STING partially rescues age-related neurological dysfunction in mice. Collectively, our findings reveal a link between mitochondrial dysfunction in microglia and cognitive aging, underscoring the significance of tightly regulated metabolism in age-associated neurological diseases.

Mitochondrial decline is a hallmark of ageing, yet the role of intergenomic compatibility in shaping ageing trajectories remains poorly understood, particularly in an ecologically relevant framework. Hormetic interventions have been proposed as strategies to modulate metabolism and lifespan, but it is unknown how this operates in the context of mitonuclear discordance. Here, we demonstrate that mitonuclear mismatch accelerates age-related mitochondrial decline, elevates reactive oxygen species production, and shortens lifespan. Strikingly, early-life mitochondrial stress induced by dietary modulation counteracts these effects, promoting mitochondrial homeostasis and longevity. Our findings reveal mitonuclear interactions shaping ageing trajectories in natural populations and provide unique evidence that targeted interventions can act as a buffer against the detrimental impact of genetic discordance.

About 1.5-2 billion years ago, an endosymbiosis between aerobic α-proteobacteria and anaerobic archaeal cells generated mitochondria, i.e., organelles capable of producing oxidative energy. The bacterial genome was fundamentally reduced and a circular mitochondrial genome evolved containing mainly the genes coding for the subunits of the electron transport chain. Before the symbiotic event, there existed a virus-host co-evolution which involved the development of sensors for detecting dangerous viral DNA/RNA molecules. Endosymbiosis supplied eukaryotic cells not only with an oxidative powerhouse to allow the evolution of more complex multicellular organisms but it also meant that cells now housed an organelle which was able to generate reactive oxygen species (ROS) and to leak mitochondrial DNA (mtDNA) and double-stranded RNA (dsRNA) into the cytoplasm. There is now abundant evidence that during aging and age-related diseases mitochondria are prone to release both mtDNA and dsRNA. In the cytoplasm, mtDNA/dsRNA molecules activate a number of cytosolic nucleic acid sensors leading to the secretion of type-1 interferons (IFN) and many other cytokines which promote an age-related proinflammatory state. Currently, it is known that mtDNA can activate the cGAS-STING pathway, AIM2 inflammasomes, IFI16 receptors, and ZBP1 sensors and in addition mitochondrial dsRNA stimulates RIG-1/MDA5 signaling. Interestingly, there is abundant evidence that all these receptors are drivers of cellular senescence and inflammaging. For decades, there has been mounting evidence that mitochondria have a crucial role in the aging process. We will examine this question from the perspective of evolution and propose that mitochondrial evolution created an endogenic source for the leakage of dangerous mtDNA/dsRNA which subsequently stimulated cytosolic DNA/RNA sensors, an evolutionarily conserved viral defence mechanism. It seems that these two evolutionary events provided not only the basis for the inevitable process of aging but also ensuring the death of parental organisms.