Mitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies

Abstract

Aging is an inherent phenomenon that is highly important in the pathological development of numerous diseases. Aging is a multidimensional phenomenon characterized by the progressive impairment of various cellular structures and organelle functions. The basis of human organ senescence is cellular senescence. Currently, with the increase in human life expectancy and the increasing proportion of the elderly population, the economic burden of diseases related to aging is becoming increasingly heavy worldwide, and an in-depth study of the mechanism of cellular aging is urgently needed. Aging, a multifactor-driven biological process, is closely related to mitochondrial dysfunction, which is the core pathological basis of a variety of age-related diseases. This article systematically reviews the molecular pathways by which mitochondrial dysfunction drives aging through multidimensional mechanisms such as metabolic reprogramming, epigenetic regulation, telomere damage, autophagy imbalance, and the senescence-associated secretory phenotype. Metabolic reprogramming promotes tumor progression and exacerbates energy metabolism disorders through abnormal activation of the PI3K/Akt/mTOR signaling pathways. The sirtuin family (such as SIRT1 and SIRT3) maintains mitochondrial homeostasis by regulating PGC-1α, FOXO3 and other targets. Telomere shortening directly inhibits mitochondrial biosynthesis through the p53–PGC-1α axis, leading to oxidative stress accumulation and a decline in organ function. The dual roles of autophagy (removing damaged mitochondria or inducing apoptosis) suggests that its homeostasis is essential for delaying aging. The SASP mediates the inflammatory microenvironment through the cGAS‒STING pathway, which is not only a marker of aging but also a driving force of disease progression. Future studies need to integrate multiomics techniques to analyze the interaction network between mitochondria and other organelles, such as the endoplasmic reticulum and lysosomes, and explore precise intervention strategies targeting sirtuins, AMPK and telomerase. Combined therapies targeting metabolic reprogramming or SASP inhibition are expected to provide new ideas for delaying aging and preventing age-related diseases.

Introduction

Human life expectancy continues to rise globally, leading to an expanding elderly population and a growing burden of age-related chronic diseases. In China, this trend is particularly pronounced, with the proportion of individuals aged 65 and older projected to surge from 12% (167 million) in 2019 to 26% (330 million) by 2050, creating unparalleled socioeconomic challenges (Chaib et al. 2022; Kumari and Jat 2021; Zhao and Stambler 2020). Aging is characterized by progressive tissue and cellular dysfunction, marked by increased susceptibility to neurodegenerative, cardiovascular, metabolic, and immune disorders (Guo et al. 2022; Roger et al. 2021).At the cellular level, mitochondrial dysfunction emerges as a central driver of senescence (Fig. 1), contributing to critical aging phenotypes including DNA damage, epigenetic dysregulation (e.g., DNA methylation and histone modifications), development of the senescence-associated secretory phenotype (SASP), and impaired intercellular communication (Feng et al. 2024; Gao et al. 2022) (Luís et al. 2022; Roger et al. 2021). Mechanisms including metabolic reprogramming, telomere attrition, and autophagy dysregulation form complex interconnected networks that drive age-related pathologies such as cancer, cardiovascular disease, and neurodegenerative disorders (L. Zhang et al. 2022; Y. Zhu et al. 2019). Although substantial evidence confirms that mitochondria regulate aging through bioenergetic failure (e.g., OXPHOS impairment), redox imbalance (ROS accumulation), and epigenetic dysregulation, current research predominantly examines these mechanisms in isolation. This leaves a critical gap in our unified understanding of their bidirectional crosstalk and synergistic interactions in cellular and organismal aging.For instance, metabolic reprogramming via the PI3K/AKT/mTOR pathway, telomere shortening—mediated mitochondrial dysfunction through the p53–PGC—1α axis, and SASP—driven inflammation via the cGAS–STING pathway are seldom integrated into a coherent framework (Sahin et al. 2011; Wan et al. 2022). This article aims to fill this gap by systematically synthesizing the latest evidence on the multidimensional mechanisms of mitochondrial dysfunction and aging. And provide comprehensive guidelines for understanding the mitochondrial basis of aging and promoting the development of anti-aging treatments by integrating molecular mechanisms.

Fig. 1.

The dynamic interactions between mitochondrial dysfunction and aging. A series of mitochondrial dysfunctions accompany the aging process, such as reduced oxidative phosphorylation (OXPHOS) activity, decreased levels of nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP), and the accumulation of tricarboxylic acid (TCA) cycle metabolites, damage-associated molecular patterns (DAMPs), and reactive oxygen species (ROS). Mitochondrial damage drives aging through multiple mechanisms including metabolic, inflammatory, and epigenetic pathways, while the aging process exacerbates mitochondrial dysfunction through damage signals feedback

Mechanisms underlying the interplay between mitochondrial metabolic reprogramming and aging

Aging-related metabolic reprogramming refers to cellular adaptations that restructure metabolic pathways to maintain bioenergetic homeostasis in the context of mitochondrial dysfunction(Fan et al. 2024), which is inherently associated with immunosenescence—a decline in immune function linked to mitochondrial dysfunction and chronic inflammation(Luís et al. 2022). In senescent cells, metabolic reprogramming favors glycolytic flux over oxidative phosphorylation (OXPHOS), a shift driven by mitochondrial respiratory chain impairment and hyperactivation of the PI3K/AKT/mTOR pathway(L. Zhang et al. 2023). Mitochondria act as both drivers and targets of metabolic reprogramming: energy metabolism dysfunction is characterized by a reduced mitochondrial OXPHOS capacity, increased reliance on glycolysis (marked by upregulated GLUT1 and HK2 expression), and decreased mitochondrial pyruvate dehydrogenase complex (PDHC) activity, leading to cytoplasmic pyruvate accumulation(Schiliro and Firestein 2021); lipid metabolic crosstalk involves mitochondrial β-oxidation defects (e.g., CPT1 downregulation) and PI3K/AKT-induced fatty acid synthesis, causing lipid droplet accumulation and damage to the mitochondrial membrane from lipid peroxidation products (e.g., 4-HNE), which results in a vicious cycle of dysfunction(Fan et al. 2024); and the immune‒metabolic axis involves the activation of NF-κB by ROS in aged immune cells (e.g., T cells), the promotion of SASP factor secretion (e.g., IL-6) and inflammatory senescence via the glycolysis–ROS‒NF-κB pathway(Luís et al. 2022). Regulatory nodes include the SIRT1/PGC-1α axis, where SIRT1 deacetylates PGC-1α to promote mitochondrial biogenesis and suppress ROS production (with an age-related decrease in SIRT1 levels locking cells into a glycolysis-dominant state)(Abu Shelbayeh et al. 2023), and the AMPK/mTOR balance, where AMPK activates mitophagy and fatty acid oxidation in response to energy stress, while mTOR inhibits autophagy and upregulates glycolytic enzymes, with the dysregulation of this axis worsening mitochondrial quality control failure(Menendez et al. 2011). Unlike tumor metabolic reprogramming (focused on proliferation), aging-associated reprogramming represents a degenerative shift toward survival under mitochondrial stress, with significant implications for tissue dysfunction and age-related diseases(Fang et al. 2023).

Glucose metabolic reprogramming

Glucose, the principal carbon substrate, provides essential bioenergetic resources for cellular maintenance and stress responses in aging, with its metabolism orchestrated via oxidative phosphorylation, glycolytic metabolism, and the pentose phosphate pathway(Fan et al. 2024; Zhang et al. 2023). In senescent cells, mitochondrial dysfunction drives a Warburg-like metabolic shift toward glycolysis over oxidative phosphorylation (OXPHOS), albeit with regulatory mechanisms distinct from those of cancer cells. This process is characterized by upregulated expression of glucose transporter 1 (GLUT1) and glycolytic enzymes (e.g., hexokinase 2, HK2), coupled with impaired mitochondrial pyruvate uptake and reduced activity of respiratory complexes I–V (Schiliro and Firestein 2021; Zhang et al. 2023). The resulting glycolytic dominance not only exacerbates mitochondrial reactive oxygen species (ROS) production but also redirects glucose-derived carbons toward lipid biosynthesis, fueling age-related lipid droplet accumulation. Activated PI3K/AKT/mTOR signaling in senescent cells promotes de novo fatty acid synthesis via acetyl-CoA carboxylase (Lasorsa et al.2023) and fatty acid synthase (FASN) while suppressing mitochondrial β-oxidation through the downregulation of carnitine palmitoyltransferase 1 (CPT1) (Fan et al. 2024; Zhang et al. 2023). This metabolic reprogramming creates a vicious cycle: lipid peroxidation products (e.g., 4-HNE) further damage mitochondrial membranes, while lipid droplets inhibit mitophagy via p62-dependent mechanisms. An imbalance between glycolysis and OXPHOS activates NF-κB signaling, amplifying the senescence-associated secretory phenotype (SASP) with proinflammatory cytokines such as IL-6 (Luís et al. 2022). A critical regulatory nexus emerges between the PI3K/AKT/mTOR and AMPK/SIRT1/PGC-1α pathways: PI3K/AKT/mTOR hyperactivation inhibits autophagy and mitochondrial biogenesis by phosphorylating ULK1 and PGC-1α (Menendez et al. 2011; Tan et al. 2016); conversely, AMPK/SIRT1 signaling counteracts this process by deacetylating PGC-1α to promote mitochondrial OXPHOS and suppress ROS production (Abu Shelbayeh et al. 2023; Ding et al. 2017). This cross-talk determines the metabolic fate of senescent cells: sustained PI3K/AKT/mTOR activation locks cells into glycolysis‒lipogenesis, whereas AMPK/SIRT1/PGC-1α reactivation restores mitochondrial homeostasis. Aged immune cells (e.g., T cells) exemplify this dysregulation, relying on glycolysis for energy despite mitochondrial dysfunction, which drives chronic inflammation and SASP propagation (Luís et al. 2022).

Lipid metabolic reprogramming

Lipids, as biomacromolecules and membrane components, function as signaling molecules and energy storage molecules, and their metabolic reprogramming is closely linked to mitochondrial dysfunction during aging (Xu et al. 2023; L. Zhang et al. 2023). In senescent cells, lipid metabolic reprogramming is characterized by imbalances in fatty acid biosynthesis, oxidation, and uptake. The PI3K/Akt signaling pathway drives the upregulation of enzymes critical for de novo fatty acid synthesis, such as acetyl-CoA carboxylase (Lasorsa et al.) and fatty acid synthase (FASN), leading to intracellular lipid droplet accumulation (Zhang et al. 2023). Acetyl-CoA, a pivotal substrate for fatty acid biosynthesis, is regulated by acyl-CoA synthetase short-chain family member 2 (ACSS2) and ATP citrate lyase (ACLY). During aging, the reduced mitochondrial β-oxidation capacity (e.g., decreased CPT1/CPT2 activity) exacerbates lipid peroxidation, generating reactive aldehydes (e.g., 4-HNE) that damage mitochondrial membranes and impair OXPHOS (Fan et al. 2024; Xie et al. 2023). Dysregulated lipid metabolism also affects mitochondrial quality control: lipid droplets in senescent cells sequester toxic lipid species but simultaneously inhibit mitophagy via p62-dependent mechanisms, creating a vicious cycle of mitochondrial dysfunction (Lasorsa et al. 2023).

Amino acid metabolic reprogramming

Amino acid metabolic reprogramming, particularly the reprogramming of glutamine metabolism, serves as a key adaptive mechanism in aging cells to maintain energy homeostasis and the redox balance (Luís et al. 2022). Glutamine metabolism supports NADPH production via malic enzyme 1 (ME1)-mediated pathways, where mitochondrial-derived malate is transported to the cytoplasm to generate reducing equivalents (Xu et al. 2023). This process mitigates oxidative stress by counteracting age-associated reactive oxygen species (ROS) accumulation (Drapela et al. 2022). The dysregulation of glutamine metabolism impairs mTOR pathway regulation and accelerates mitochondrial dysfunction (Martin-Montalvo and de Cabo 2013), contributing to cellular senescence (Luís et al. 2022).

Metabolic reprogramming

The sirtuin family has antiaging effects

Sirtuins (SIRT1-7), evolutionarily conserved NAD⁺-dependent deacetylases, act as central hubs linking metabolic homeostasis and aging by regulating mitochondrial function, epigenetic modifications, and autophagic pathways (Martin-Montalvo and de Cabo 2013; Sack and Finkel 2012). Mitochondrial SIRT3-5, particularly SIRT3, directly maintain mitochondrial integrity by deacetylating key metabolic enzymes (e.g., SOD2 and respiratory chain complexes) to increase oxidative phosphorylation (OXPHOS) and reduce reactive oxygen species (ROS) production. For example, SIRT3-mediated deacetylation of TFAM (mitochondrial transcription factor A) strengthens its binding to mtDNA, stabilizing mitochondrial genome replication and transcription (Alexeyev 2023). Concurrently, SIRT3 activates the FOXO3a–PINK1–Parkin axis to promote mitophagy, clear damaged mitochondria and prevent ROS-induced dysfunction (Wan et al. 2022).

Nuclear/cytosolic SIRT1 indirectly regulates mitochondrial biogenesis by deacetylating PGC-1α, a master coactivator of mitochondrial transcription. This interaction enhances PGC-1α binding to nuclear respiratory factor 1 (NRF-1), driving mtDNA replication and OXPHOS-related gene expression (Abu Shelbayeh et al. 2023). Additionally, SIRT1 suppresses NF-κB-mediated inflammation and activates antioxidant pathways (e.g., HO-1), creating a protective milieu for mitochondrial function under oxidative stress (Schiliro and Firestein 2021).

The antiaging effects of sirtuins are tightly linked to NAD⁺ availability, as an age-related decrease in NAD⁺ levels impairs SIRT1/3 activity and disrupts the PGC-1α–TFAM–mitochondrial biogenesis feedback loop (Drapela et al. 2022). Therapeutically, SIRT3 activators improve mitochondrial function in aging cardiac myocytes, whereas SIRT1 agonists such as resveratrol enhance neuronal mitochondrial quality control in neurodegenerative models (Abu Shelbayeh et al. 2023; Wan et al. 2022). However, challenges in tissue-specific delivery and potential oncogenic risks (e.g., the dual roles of SIRT1 in cancer) necessitate the development of targeted sirtuin modulators.

Cellular signaling pathways associated with metabolic reprogramming

IL-6 receptor activation initiates JAK/STAT3 signaling, triggering STAT3 phosphorylation and nuclear translocation to modulate gene expression. Concurrently, the PI3K/Akt/mTOR pathway orchestrates tumor metabolic reprogramming by upregulating glycolysis and oxidative phosphorylation while suppressing autophagy—dual mechanisms that drive cancer progression through increased energy production and therapy resistance (Tan et al. 2016). AMPK maintains cellular energy homeostasis by sensing AMP/ATP ratios, inhibiting anabolic processes while promoting fatty acid oxidation to support tumor cell bioenergetics (Martin-Montalvo and de Cabo 2013). Hypoxia stabilizes HIF-1α, driving anaerobic glycolysis and activating angiogenesis (e.g., VEGF) to increase tumor perfusion (Kubicka et al. 2021). The Wnt family comprises 19 secreted glycoproteins that transmit signals by binding to Frizzled receptors, operating through both β-catenin-dependent (canonical) and -independent (noncanonical, including planar cell polarity [PCP] and Wnt/Ca²⁺) signaling pathways. Genetic/epigenetic alterations in these pathways lead to aberrant Wnt/β-catenin activation, contributing to oncogenesis and disease progression (Hayat et al. 2022). Canonical Wnt signaling drives metabolic reprogramming via the TCF/LEF-mediated upregulation of MCT-1, CYC1, and ATP synthase, promoting lactate export and aerobic glycolysis. Concurrently, Wnt/c-Myc activation transcriptionally amplifies GLUT-1, LDH, PKM2, and SLC1A5 to increase glycolytic flux, nucleotide synthesis, and lipid biosynthesis in cancer cells. Parallel noncanonical Wnt signaling sustains aerobic glycolysis through Akt‒mTOR pathway activation, stabilizing mTORC1 and β-catenin to increase glucose transporter expression. mTOR further coordinates anabolic metabolism by facilitating acetyl-CoA-dependent fatty acid biosynthesis, activating glucose-6-phosphate dehydrogenase (G6PD) to amplify nicotinamide adenine dinucleotide phosphate (NADPH), which is critical for lipid anabolism and nucleic acid production via the pentose phosphate pathway (Mo et al. 2019).

Epigenetic regulation: dynamics of aging at the chromatin level

Epigenetics

Epigenetic mechanisms play a central role in orchestrating aging trajectories and significantly influence the pathogenesis of diverse age-related diseases (Bueno et al. 2020). Epigenetic mechanisms critically regulate aging trajectories through dynamic DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA (ncRNA)-mediated pathways, directly influencing age-related disease pathogenesis (Wang et al. 2024; Xu et al. 2023). These reversible modifications orchestrate cellular senescence without altering DNA sequences, with sirtuins serving as pivotal epigenetic enzymes that mediate aging processes and caloric restriction responses (Zhu et al. 2021). Crucially, mitochondrial dysfunction (e.g., altered NAD⁺/α-KG levels) drives epigenetic dysregulation, establishing a bidirectional link between metabolic stress and age-related chromatin changes (Shi et al. 2022; Zhu et al. 2021).

Epigenetic regulation

Epigenetic regulation integrates mitochondrial dysfunction with hallmark aging phenotypes—including inflammation, metabolic shifts, and genomic instability—through three primary mechanisms: 1. oxidative stress- and NAD⁺ depletion-driven DNA methylation alterations (Xu et al. 2023); 2. mitochondrial metabolite-modulated histone modifications (e.g., α-KG/acetyl-CoA-regulated H3K9ac/H3K27me3) (Shi et al. 2022); 3. ncRNA-mediated pathways that amplify the SASP via mitochondrial ROS (Wang et al. 2022a, b, c).

DNA methylation: a dynamic epigenetic landscape

DNA methylation, a crucial epigenetic mechanism, transmits genetic information to the DNA of offspring by regulating DNA methyltransferases (DNMTs) (Shi et al. 2022). This process involves the covalent binding of methyl groups to cytosine residues in DNA at CpG sites (Mahmoud 2022). It denotes the covalent attachment of a methyl group to the 5ʹ carbon position of cytosine—predominantly within CpG dinucleotides or CpG-rich genomic regions—thereby altering the DNA structure and modulating transcription factor binding to induce changes in target gene transcriptional profiles (Wang et al. 2022a, b, c). Enzymes involved in DNA methylation are classified into three functional categories: writing enzymes, erasing enzymes, and reading enzymes (Shi et al. 2022; Wang et al. 2022a, b, c). DNA methylation primarily occurs as cytosine methylation at the 5ʹ carbon position (5-methylcytosine, 5mC) within CpG dinucleotides, representing one of the earliest identified and most studied epigenetic modifications (Xu et al. 2023). In eukaryotic cells, DNA methylation acts as a key mechanism governing gene expression, particularly in mammalian systems. The UHRF family of proteins maintains DNA methylation by recruiting DNMT1 to semimethylated DNA during replication (Shi et al. 2022). With organismal aging, transposon-associated CpG sites tend to lose methylation, whereas promoter CpG sites gain methylation, leading to overall DNA hypomethylation (Soto-Palma et al. 2022). While most epimutations affect introns or intergenic regions, the methylation and silencing of specific tumor suppressor genes (e.g., p16 and p53) can drive tumor initiation and progression (López-Otín et al. 2023).

Histone modifications: remodeling chromatin for aging

Histones are fundamental proteins that compact DNA into chromatin, regulating gene accessibility and transcriptional activity. Posttranslational modifications of histones—including methylation, acetylation, phosphorylation, ubiquitination, and ADP-ribosylation—serve as dynamic regulators of chromatin structure and function. These modifications alter histone‒DNA interactions, shifting chromatin between transcriptionally active (open) and repressive (condensed) states (Shi et al. 2022; Wang et al. 2024). Acetylation, a well-characterized modification, occurs at lysine residues on the tails of histones H3 and H4. By neutralizing the positive charge of lysine, acetylation reduces electrostatic interactions with negatively charged DNA, loosening chromatin to facilitate transcriptional activation. Conversely, deacetylation by histone deacetylases (HDACs) restores chromatin compaction, which silences gene expression (la Torre et al. 2023; Xu et al. 2023). Enzymes governing histone modifications are categorized as “writers” (e.g., histone acetyltransferases, HATs; methyltransferases, HMTs), “erasers” (e.g., HDACs; demethylases, HDMs), and “readers” (proteins recognizing specific modifications), which collectively maintain epigenetic homeostasis (Mahmoud 2022; Wang et al. 2022a, b, c). Notably, sirtuins, a subclass of NAD⁺-dependent HDACs, modulate aging and cancer by deacetylating histones and nonhistone targets (Zhu et al. 2021). Age-related dysregulation of histone modifications, such as the global loss of heterochromatin and altered acetylation patterns, disrupts transcriptional programs, leading to metabolic dysfunction and cellular senescence. For example, aberrant histone acetylation in aging cells promotes proinflammatory gene expression and mitochondrial dysfunction, exacerbating age-related pathologies (López-Otín et al. 2023; Wang et al. 2022a, b, c). Similarly, cancer cells exhibit tissue-specific histone modification profiles that drive oncogenic transcription and metabolic reprogramming, highlighting the dual roles of epigenetic alterations in aging and disease (Mahmoud 2022).

Chromatin remodeling: mechanisms of genomic instability

ATP-dependent chromatin remodeling represents an epigenetic mechanism regulating gene expression at the chromatin level (Wang et al. 2022a, b, c). Chromatin reorganization modulates DNA accessibility to the transcriptional machinery through ATP-dependent chromatin remodelers, such as the imitation switch (ISWI) complex, which is a conserved member of the SWI2/SNF2 superfamily. These molecular machines dynamically restructure nucleosome positioning by remodeling histone‒DNA interactions, enabling transcriptional modulation while maintaining the chromatin architecture—a critical mechanism for genomic regulation and transcriptional precision. Numerous senescence-associated chromatin remodeling factors, including brahma-related gene 1 (BRG1), which encodes the ATPase subunit of the SWI/SNF chromatin remodeling complex, have been identified. Altered BRG1 expression—via gene silencing or overexpression—induces cellular senescence in human and rat mesenchymal stem cells (MSCs) (Zhang et al. 2021).

ncRNA regulation: posttranscriptional control of aging

ncRNAs are RNA molecules that do not encode proteins and include ribosomal RNA (rRNA), transfer RNA (tRNA), small nuclear RNA, small nucleolar RNA, microRNA (miRNA), and long noncoding RNA (lncRNA). Among these, miRNAs and lncRNAs are the most studied (Fitz-James and Cavalli 2022). MicroRNAs are small (~ 22 nucleotides) molecules that regulate gene expression posttranscriptionally. For example, multiple miRNAs, such as miR-30, miR-26b, miR-199a, and miR-148a, participate in adipogenesis (Mahmoud 2022). These noncoding transcripts exhibit conserved genomic integration through transcription while bypassing protein synthesis, executing their functions via ribonucleoprotein complexes at the transcript level (Mahmoud 2022). Noncoding RNAs (ncRNAs) constitute approximately 80% of the human genome and encompass millions of regulatory regions. Emerging evidence highlights their pivotal roles in epigenetic regulation, gene expression, and cancer-associated metabolic reprogramming (Xu et al. 2023).

Telomere dysfunction

Telomere dysfunction and its bidirectional interaction with mitochondrial dysfunction in aging

Telomeres are repeat sequences of TTAGGGn in DNA situated at the terminal ends of linear chromosomes in eukaryotic organisms that maintain chromosomal integrity and help control cell division cycles. During the aging process, telomere shortening and mitochondrial dysfunction are two central drivers of cellular senescence. These processes form a vicious cycle through bidirectional interactions, jointly accelerating aging and the progression of related diseases such as cardiovascular disorders, neurodegenerative diseases, cancer, and metabolic syndrome (Zhu et al. 2019). During senescence, telomeres play important roles as targets of the DNA damage response. Telomere shortening is a critical determinant of a species lifespan (Roger et al. 2021). Telomerase elongates the telomere by appending repetitive DNA sequences to the termini of chromosomes, with its catalytic core consisting of telomerase reverse transcriptase and a telomerase RNA component (TERC). Thus, normal cellular telomere function relies on both structural integrity and telomerase activity. Telomere erosion acts as a defining feature of cellular aging, inducing cellular dysfunction or triggering apoptosis, whereas telomere integrity safeguards chromosome ends and maintains genomic stability (Wang et al. 2021).

FOXC1, an essential transcription factor during early cardiogenesis, exhibits elevated expression in senescent telomere-dysfunctional cardiac myocytes (sTL-CMs), with its protein abundance demonstrating an inverse correlation with telomere length in heart failure patients. Shortened telomeres lead to increased chromatin accessibility, which induces FOXC1-dependent expression networks, leading to systolic dysfunction and myocardial aging. Experiments in aging human fibroblasts have shown that shortened telomeres can produce DNA damage signals, potentially linked to low gene expression and histone loss (la Torre et al. 2023). Telomere shortening progresses incrementally during cell division due to the end-replication problem, with extremely shortened telomeres eliciting a persistent DNA damage response (DDR) that culminates in cellular senescence or apoptotic cell death (Yang et al. 2024; Chistiakov et al. 2018). The p38 MAP kinase acts as a central orchestrator of DDR pathways, where its phosphorylation initiates NF-κB transcriptional activation cascades that drive senescence-associated secretory phenotype (SASP)-related transcriptional programs. Pharmacological suppression of p38 signaling attenuates SASP component biosynthesis and release, particularly that of proinflammatory cytokines (Zhu et al. 2021). Short telomeres compromise the stem cell regenerative capacity, leading to tissue aging, whereas DDR activation induces cell cycle arrest via the p53‒p21 and p16INK4A‒pRb pathways, which govern cellular senescence (Farfariello et al. 2022; Gao et al. 2022; Vizioli et al. 2020).

Telomerase, a unique enzyme that extends telomeres via repetitive DNA addition, has a catalytic core comprising telomerase reverse transcriptase and TERC (Birch and Gil 2020; Li et al. 2023). Telomere dysfunction initiates p53-dependent signaling, with p53 directly repressing the PGC-1α and PGC-1β regulatory regions, linking the telomere status to mitochondrial homeostasis. This telomere–p53–PGC axis drives multiorgan dysfunction and metabolic deterioration under conditions of telomere attrition (Sahin et al. 2011). Extremely short telomeres trigger a sustained DDR, inducing senescence via p53-mediated replicative arrest while inhibiting PGC-1α, a key regulator of mitochondrial biogenesis, leading to dysfunctional mitochondrial accumulation and a bioenergetic imbalance (Gonzales-Ebsen et al. 2017).

Studies have shown that telomere shortening is a primary trigger of chromosome damage in oxidatively stressed T lymphocytes, with nuclear DNA damage strongly correlated with the mitochondrial DNA copy number (mtDNAcn), reinforcing the telomere–mitochondrial axis as a modulator of age-related diseases (Borghini et al. 2024). Telomere DNA damage via p53 signaling inhibits the mitochondrial regulators PGC-1α and TFAM, contributing to mitochondrial dysfunction through impaired oxidative phosphorylation and ATP synthesis (Wang et al. 2021).

Telomere attrition and mitochondrial dysfunction: interaction and mechanisms

Telomere attrition and genomic instability at chromosomal termini are established drivers of replicative senescence and organismal aging. Clinical manifestations of physiological aging often correlate with the accelerated erosion of telomeric integrity (Rossiello et al. 2022). Pathological activation of p53-dependent growth arrest pathways, replicative senescence programs, and apoptotic mechanisms via a telomere crisis underlie progressive tissue degeneration and functional impairment, particularly in rapidly renewing organ systems (Sahin et al. 2011). Telomere shortening and mitochondrial dysfunction are long-recognized primary initiators of natural aging (Zhu et al. 2019). Telomere shortening leads to mitochondrial malfunction (Fig. 2), with the “telomere–mitochondria–senescence” axis significantly influencing this process. Telomere attrition is linked to a mitochondrial impairment through three defined signaling pathways: the “telomere–p53–PGC-1α/β” pathway, the “NAD⁺–SIRT1–PGC-1α” pathway, and the “ATM–AKT–mTOR–PGC-1β” pathway (Atayik and Çakatay 2023; Wang et al. 2024). In mammalian aging models, telomere-associated damage foci (TAFs) arise in terminally differentiated cardiac myocytes via mechanisms independent of telomere attrition. This age-related phenomenon is correlated with the coordinated upregulation of the cyclin-dependent kinase inhibitors p16INK4a and p21CIP1 while triggering the activation of a cardiac-enriched senescence-associated secretory phenotype (SASP) that drives pathological remodeling in myocardial hypertrophy and fibrosis (Rossiello et al. 2022). Telomere damage induces mitochondrial biosynthesis reprogramming and dysfunction via p53 activation, which directly represses the promoters of PGC-1α and PGC-1β—key regulators of mitochondrial physiology and metabolism. Conversely, mitochondrial dysfunction promotes both telomere loss and the formation of telomere dysfunction-induced foci (TIFs), where DNA damage response factors accumulate at critically short or uncapped telomeres (Lin and Epel 2022).

Fig. 2.

Telomere dysfunction regulates mitochondrial biogenesis and function

Telomere attrition regulates mitochondria via the PARP1–NAD+–SIRT1, ATM/R–P53–PGC1α/β and ATM–AKT–mTOR–PGC1β pathways. The activation of these pathways ultimately results in mitochondrial dysfunction and increased reactive oxygen species (ROS) levels. The combined effects of telomere and mitochondrial dysfunction ultimately drive the aging process.

Roles of sirtuins, epigenetic modifications and telomere integrity in aging

Sirtuins are proteins that delay aging and alleviate age-related diseases through diverse molecular pathways, including retarding telomere shortening (Wan et al. 2022). Epigenetic modifications, such as DNA methylation, histone modifications, and chromatin remodeling, regulate gene expression without altering the DNA sequence, driving age-related chromatin changes such as heterochromatin loss and redistribution. Pericentric heterochromatin assembly requires H3K9 and H4K20 trimethylation and heterochromatin protein 1α (HP1α) binding, whereas telomeric regions exhibit similar modifications, linking chromosomal end integrity to heterochromatin-mediated aging mechanisms (Menendez et al. 2011; Wang et al. 2022a, b, c). The NAD+-dependent deacetylase SIRT1 translocates to nuclear lesion sites under stress, orchestrating chromatin relaxation for error-free DNA repair and mitigating mutagenic cascades in aging-related pathologies (Li et al. 2023).

Autophagy changes

Autophagy

Autophagy, a conserved catabolic process, maintains cellular homeostasis by degrading damaged organelles via lysosomal fusion, with its activation mediated by the ULK1–ATG13–FIP200 complex and suppression mediated by mTOR signaling (Hashemi et al. 2023; Yurube et al. 2024). In mitophagy, the selective clearance of mitochondria occurs through Parkin-dependent pathways (PINK1 stabilization → Parkin phosphorylation → OMM protein ubiquitination → p62-mediated autophagosome recruitment) and receptor-mediated pathways (NIX/FUNDC1/BNIP3-driven autophagosome recruitment via adaptors) (Wang et al. 2022a, b, c). Mitophagic flux is regulated by sirtuins (e.g., SIRT3), which enhance PINK1/Parkin signaling and mitochondrial fission, and the PGC-1α–TFAM axis, where PGC-1α activates NRF/ERRs to induce TFAM, sustaining mtDNA integrity (Wan et al. 2022). Critically, an age-related decline in PGC-1α–TFAM activity impairs mitophagy, accelerating dysfunctional organelle accumulation and driving aging pathologies (Prasun 2020; Wan et al. 2022).

mTOR inhibitors and autophagy activators

mTOR is a central regulator of autophagy and aging, and it suppresses autophagic flux to drive senescence while integrating signals from the sirtuin, AMPK, insulin/IGF-1, and FOXO pathways (Kennedy and Lamming 2016). Growth factor-activated PI3K/AKT signaling phosphorylates and activates mTOR, inhibiting autophagy initiation (Wan et al. 2022). Critically, mTOR inhibitors (e.g., rapamycin) counteract this suppression, enhancing mitophagy to clear dysfunctional mitochondria and attenuate DNA damage-induced senescence—directly linking mTOR modulation to mitochondrial quality control and longevity (Menendez et al. 2011; Nair and Ren 2012).

Activation of autophagy

Mitochondria undergo mitophagy, reducing oxidative stress/DNA damage to delay senescence, while excessive flux may trigger apoptosis (Li et al. 2024). Importantly, the autophagy-mediated clearance of mitochondrial-derived chromatin fragments (CCFs) suppresses cGAS/STING-driven SASP-mediated inflammation, mitigating the age-related decline (Li et al. 2024). Furthermore, autophagy‒lysosome efficiency determines the removal of cytotoxic aggregates, with impaired flux (e.g., VPS35 deficiency) accelerating proteotoxic stress in individuals with age-related diseases (Menendez et al. 2011).

SASP

The senescence-associated secretory phenotype (SASP) amplifies age-related inflammation through the mitochondrial dysfunction-driven secretion of proinflammatory cytokines (e.g., IL-6 and IL-8), proteases, and growth factors (Luís et al. 2022). Mitochondrial damage releases mtDNA and ROS (mtDAMPs), activating cGAS–STING–NF-κB signaling to transcriptionally upregulate SASP components (Suryadevara et al. 2024). Epigenetic mechanisms further regulate the SASP, with hypomethylation of *IL6/IL8/CXCL1* promoters increasing their expression in senescent cells (Roger et al. 2021). This mtDAMP‒SASP‒inflammation axis establishes a vicious cycle that accelerates tissue degeneration during cardiovascular and neurodegenerative aging (Fig. 3).

Fig. 3.

Mitochondrial dysfunction leads to age-related diseases. When mitochondria are subjected to stress stimuli, they release mitochondrial damage-associated molecular patterns (mtDAMPs), such as mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (mtROS). These mtDAMPs activate specific signaling pathways (e.g., the cGAS–STING pathway or NLRP3 inflammasome), triggering the release of inflammatory factors. Sustained chronic inflammation ultimately contributes to the development of various age-related diseases

Mitochondria-linked senescence mechanisms

Senescent cells undergo irreversible cell cycle arrest via the p53/p21CIP1 and p16INK4a/RB pathways, which inhibit cyclin-dependent kinases (CDKs) in a process amplified by mitochondrial dysfunction (Birch and Gil 2020). Mitochondrial damage triggers macromolecular alterations that activate NF-κB signaling, drive SASP secretion of proinflammatory cytokines and chemokines (Luís et al. 2022), promote senescence through autocrine/paracrine SASP factors (e.g., IL-6 and CXCL1), and recruit immune cells while inducing bystander senescence in neighboring cells (Ohtani 2022).

Mitochondrial induction of the SASP

Mitochondrial outer membrane permeabilization (MOMP) releases mtDNA into the cytosol, activating the cGAS–STING pathway to trigger the inflammatory SASP through the TBK1-dependent phosphorylation of IRF3 and NF-κB, which drives interferon and cytokine production (Birch and Gil 2020; Suryadevara et al. 2024) (Fig. 3). Concurrently, p38 MAPK amplifies the SASP by enhancing NF-κB activity, linking mitochondrial dysfunction to age-related immune dysregulation (Birch and Gil 2020). Nuclear genomic instability (e.g., accumulated DNA fragments) synergistically potentiates this pathway in aged cells (Ohtani 2022).

Transcriptional control of the SASP

mTOR integrates mitochondrial metabolic stress into SASP transcriptional regulation through three synergistic mechanisms, forming a positive feedback network that promotes aging and inflammation:

i. Inhibiting autophagy-lysosomal function, impeding the clearance of damaged organelles (such as mitochondria), and promoting SASP factor packaging and secretion via TASCC structures to continuously stimulate SASP production (Birch and Gil 2020);

ii. Mediating the translational activation of IL-1α to drive the transcription of proinflammatory cytokines (e.g., IL-6 and IL-8) through the NF-κB pathway, forming a "mitochondrial damage‒inflammation" positive feedback loop (Birch and Gil 2020).

iii. Phosphorylating MAPKAPK2 to inhibit the ZFP36L1-mediated degradation of SASP-related mRNAs and increase inflammatory signal stability (Birch and Gil 2020).

This network establishes a self-reinforcing SASP–DNA damage response (DDR) circuit that amplifies mitochondrial dysfunction and inflammatory aging (Rossiello et al. 2022).

Aging and SASP-promoted diseases

The senescence-associated secretory phenotype (SASP) is indispensable for mediating the detrimental effects of senescent cells. Through the secretion of proinflammatory factors, chemokines, proteases, and growth factors, the SASP actively drives tissue degeneration and dysfunction (Birch and Gil 2020; Cui et al. 2022). Crucially, eliminating senescent cells is necessary to reduce the burden of these pathogenic SASP factors. The failure to eliminate senescent cells leads to the progressive depletion of functional cell populations, including stem and progenitor cells, severely compromising tissue repair and the regenerative capacity (Birch and Gil 2020; Cui et al. 2022). Senescent cells and their SASP mediators drive pathological progression through coordinated mechanisms, including extracellular matrix remodeling, modulation of immune cell infiltration, and reprogramming of tissue-resident cell differentiation trajectories (Ohtani 2022). This multifaceted pathological transformation underlies many age-related diseases. Therapeutic strategies targeting SASP-promoted pathologies include the following:

i. Natural compounds—quercetin, for example, exerts protective effects by enhancing mitochondrial integrity through the activation of SIRT1- and PINK1-mediated mitophagy, the suppression of cytochrome C release, the modulation of cystatin C, the regulation of the Bcl2/Bax balance, the inhibition of apoptosis-inducing factor (AIF) nuclear translocation, and the promotion of neuronal survival via autophagy activation and microenvironment modulation, thereby countering age-related apoptosis (Cui et al. 2022).

ii. Targeted senotherapeutics—bromodomain and extraterminal domain protein degraders (BET degraders or BETds) represent a novel class of dual-mechanism senotherapeutics. They induce irreversible cell cycle arrest in senescent cells by suppressing nonhomologous end joining (NHEJ) and simultaneously enhancing autophagic flux (Ohtani 2022). Senomorphics: These agents are a multimodal pharmacological intervention that target core SASP regulators, including NF-κB, JAK-STAT, mTOR, and mitochondrial complex I/IV-mediated retrograde signaling. Translational studies have confirmed that NF-κB pathway-specific antagonists effectively suppress proinflammatory cytokine networks in vitro and in vivo, demonstrating significant therapeutic potential through the selective modulation of the senescence-associated secretory circuitry (Chaib et al. 2022).

Mitochondrial dysfunction and cardiovascular disease

Aging significantly increases the risk of chronic diseases associated with mitochondrial dysfunction, particularly cardiovascular disorders such as atherosclerosis, hypertension, and heart failure (Atayik and Çakatay 2022; Chistiakov et al. 2018; Atasever et al. 2022). As a primary driver of cardiovascular aging, mitochondrial dysfunction is correlated with an increased incidence of heart failure and coronary artery disease (Dookun et al. 2022). Global data indicate that cardiovascular diseases (CVDs) remain the leading cause of death, with an estimated 23.6 million deaths by 2030, and these diseases are strongly linked to mitochondrial oxidative stress and senescence (Bhatti et al. 2023; Li et al. 2024).

Mitochondrial redox imbalance drives age-related cardiac senescence through the formation of telomere-anchored DNA damage foci (TAFs) in cardiomyocytes, a process that is independent of telomere shortening but dependent on mitochondrial dysfunction (Dookun et al. 2022). Reduced SIRT3 activity exacerbates vascular dysfunction in individuals with hypertension, which is characterized by impaired nitric oxide signaling and HIF1α-mediated inflammation, via increased acetylation and inactivation of the antioxidant enzyme SOD2 (Mongelli et al. 2023).

In cardiac remodeling, SIRT3-mediated deacetylation of FOXO3 activates PGC-1α, a master regulator of mitochondrial biogenesis and mitophagy, to counteract dysfunctional mitochondria and oxidative stress (Wan et al. 2022). Concurrently, AMPK signaling enhances mitochondrial bioenergetics by promoting SIRT1-dependent FOXO3 activation, linking energy metabolism to antiapoptotic pathways via Bcl-2/Bax regulation (Sack and Finkel 2012; Ho et al. 2022).

Mitochondrion-targeted anti-aging strategies

Mitochondrial dysfunction drives aging and serves as a critical therapeutic target, with age-related pathologies closely linked to mitochondrial dysfunction and cellular senescence. The key anti-aging approaches include the following: 1. Senolytics (eliminating senescent cells)—The BCL-2 inhibitor ABT263 selectively clears senescent cells by targeting mitochondrial proapoptotic proteins such as BCL-XL. 2. Senomorphics (suppressing the SASP)—Mitochondrion-targeted antioxidants (e.g., MitoQ and SS-31) reduce ROS levels and inhibit the NF-κB inflammatory pathway (Atayik and Çakatay 2022). Naturally occurring senolytics and senomorphics, such as resveratrol and curcumin, have the potential to delay aging in cellular and animal models. However, the clinical evidence remains limited, necessitating further research to validate their safety and efficacy (Luís et al. 2022). The clinical utility of most newly synthesized therapeutics is limited due to individual-specific and organ-specific variations in senescent phenotypes and adverse effects. These limitations collectively highlight the necessity for further clinical investigations to identify effective senotherapeutic interventions, such as metformin, for age-related diseases (Dookun et al. 2022). By targeting specific SASP-associated signaling pathways, metformin may provide novel therapeutic benefits to mitigate the detrimental effects of senescent cell accumulation in the most prevalent geriatric ARDs (Turgut et al. 2025). The mechanisms of action of various mitochondrion-targeted therapeutics are summarized in Table 1.

Table 1.

Mitochondrion-targeted senotherapeutic agents

Drug type	Representative drug	Target/mechanism	Effect(s)
Senolytics	ABT263	Targets BCL-XL, induces apoptosis in senescent cells	Reduces the senescent cell burden
Senomorphics	MitoQ	Mitochondrion-targeted antioxidant, inhibits NF-κB	Attenuates SASP-mediated inflammation, improves the mitochondrial membrane potential
Natural compounds	Resveratrol	Activates SIRT1/AMPK signaling, enhances mitophagy	Boosts mitochondrial function, delays metabolic aging

Conclusions and future perspectives

Aging, a multifactorial biological process closely associated with mitochondrial dysfunction, serves as the core pathological basis for various age-related diseases. This review systematically elucidates the molecular pathways through which mitochondrial dysfunction drives aging via multidimensional mechanisms, including metabolic reprogramming, epigenetic regulation, telomere attrition, autophagy dysregulation, and the senescence-associated secretory phenotype (SASP). Metabolic reprogramming promotes tumor progression and exacerbates energy metabolism disorders through the aberrant activation of PI3K/Akt/mTOR signaling pathways. The sirtuin family (e.g., SIRT1 and SIRT3) maintains mitochondrial homeostasis by regulating targets such as PGC-1α and FOXO3. Telomere shortening directly suppresses mitochondrial biogenesis via the p53–PGC-1α axis, leading to oxidative stress accumulation and a decline in organ function. The dual roles of autophagy (clearing damaged mitochondria versus inducing apoptosis) highlight the critical importance of its dynamic equilibrium in delaying aging. The SASP mediates inflammatory microenvironments through the cGAS–STING pathway, serving both as a hallmark of senescence and a driver of disease progression. Future research should integrate multiomics technologies to decipher mitochondrial interaction networks with other organelles (e.g., the endoplasmic reticulum and lysosomes) and explore precision intervention strategies targeting sirtuins, AMPK, and telomerase. Combination therapies targeting the regulation of metabolic reprogramming or SASP inhibition may provide novel approaches for delaying aging and preventing age-related diseases.

Author contribution

Pei Wei: Responsible for the overall writing direction of this review and the structure of the article, responsible for the abstract and the first part of the content of the article. Part 2. Part 3 and Conclusions. Siyu Sun: Responsible for introducing this review and revising the overall content. Chi Yan: Responsible for drawing and part 4 of this review. Xiaoyan Zhang: Responsible for part 5 of this review. Zhigang Chen: Responsible for part 6 of this review. Fei Lin: Responsible for the review and the school team.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.