bims-mihora 2026-04-05 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–04–05
thirteen papers selected by
Lisa Patel, Istesso

ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.
Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.
ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.
Unexpected role of the integrated stress response in cancer immune evasion.
NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.
Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
Identification and verification of biomarkers associated with integrated stress response in heart failure.
The IGF-1 senescence switch: a biphasic model for SASP-driven aging and precision senomodulation.
Mesenchymal stromal cells and their derivatives: A regenerative frontier in burn wound healing.
Telocytes in skeletal muscle: Emerging players in homeostasis and repair/regeneration.
Reprogramming the mitochondrial-circadian energy code with incretins.
The case for space as a model of accelerated aging.

Aging (Albany NY). 2026 Mar 27. 18(1): 213-233

ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.

Victoria C Sanfrancesco, David A Hood.

  In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging. To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body KO and WT male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial ROS production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance. Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.

Keywords:  ATF5; aging; mitochondria; skeletal muscle; stress response

DOI:  https://doi.org/10.18632/aging.206365
Aging Cell. 2026 Apr;25(4): e70452

Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.

Amélia Lalou, Ioanna Daskalaki, Ilias Gkikas, Sandra Rodríguez-López, Jean-David Morel, Giorgia Benegiamo, Adrien Faure, Arwen W Gao, Joaquim Barmaz, Qi Wang, Terytty Yang Li, Feng Gao, Danaé Broustail, Kristina Schoonjans, Giovanni D'Angelo, Johan Auwerx.

  Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.

Keywords:   Caenorhabditis elegans ; aging; doxycycline; drug repositioning; longevity; miglustat; mitochondria; terbinafine

DOI:  https://doi.org/10.1111/acel.70452
bioRxiv. 2026 Mar 25. pii: 2026.03.20.711686. [Epub ahead of print]

Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.

Lucía Fernández-Del-Río, Andrea Eastes, David Rincón Fernández Pacheco, Nikole Scillitani, Jasmine Garza, Matthew Dugan, Matheus Pinto de Oliveira, Pradnya Kadam, Iman Gauhar, Karel Erion, Kathleen Rodgers, Kevin Gaffney, Amy Wang, Marc Liesa, Cristiane Benincá, Orian Shaul Shirihai.

Primary mitochondrial diseases are clinically and genetically heterogeneous disorders, commonly caused by defects in the oxidative phosphorylation system. This heterogeneity presents major challenges for therapeutic development; however, a shared hallmark across these diseases is the accumulation of dysfunctional mitochondria. Enhancing mitochondrial turnover, by activating the selective degradation of dysfunctional mitochondria via mitophagy, concurrently with the activation of mitochondrial biogenesis, could represent a shared therapeutic strategy for mitochondrial diseases. Here, we describe a novel mitophagy inducer, CAP-1902. CAP-1902 is a new agonist of the MAS G-Protein Coupled Receptor (MasR). In fibroblasts from patients carrying a BCS1L mutation that impairs complex III (CIII) assembly, CAP-1902 increased mitochondrial turnover by promoting both mitophagy and biogenesis. Specifically, MasR activation triggered the AMPK/ULK1/FUNDC1 mitophagy pathway. Knockdown of FUNDC1 blocked mitophagy but not AMPK activation, confirming pathway specificity. Additionally, a decrease in the occurrence of depolarized mitochondria with treatment indicated the selective targeting of accumulated damaged mitochondria in the disease context. MasR activation by CAP-1902 also stimulated the nuclear translocation of PGC-1α, promoting increased expression of transcripts associated with mitochondrial biogenesis, respiratory chain components, and mitochondrial translation. Remarkably, CAP-1902 was ultimately able to restore key defects in CIII-deficient fibroblasts by rescuing bioenergetics and correcting both the aberrant lysosomal distribution and the elevated integrated stress response markers, which is consistent with a shift toward a healthier mitochondrial population. In summary, we describe the first potential GPCR-mediated treatment of mitochondrial diseases and demonstrate that MasR activation by CAP-1902 induces mitochondrial turnover and improves mitochondrial function.

DOI: https://doi.org/10.64898/2026.03.20.711686
bioRxiv. 2026 Mar 28. pii: 2026.03.27.711928. [Epub ahead of print]

ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.

Amber Crabtree, Mohd Mabood Khan, Estevao Scudese, Calixto Pablo Hernandez Perez, Prasanna Venkhatesh, Andrea G Marshall, Benjamin Rodriguez, Edgar Garza Lopez, Okwute M Ochayi, Estélio Henrique Martin Dantas, Pamela Martin, Matheus Baffi, Fabiana Scartoni, Margaret Mungai, Kit Neikirk, Jennifer Streeter, Renata Oliveira Pereira, Dao Fu Dai, Han Le, Harrison Mobley, Jeremiah Afolabi, Bret C Mobley, Celestine N Wanjalla, Duane Hall, Julia Berry, Oleg Kovtun, Jenny C Schafer, Sean Schaffer, Prasanna Katti, Chantell Evans, Andre Kinder, Joyonna Gamble George, Melanie McReynolds, Annet Kirabo, Sepiso Kenias Masenga, Antentor Hinton.

Aging is associated with a progressive loss of skeletal muscle function, known as sarcopenia; however, the molecular mechanisms coordinating cellular stress responses and structural adaptations remain incompletely understood. The aim of this study was to investigate the role of activating transcription factor 4 (ATF4), a master regulator of the integrated stress response (ISR), in aging muscle using complementary human population and mouse model approaches. Older adults exhibited a marked decrease in aerobic capacity, muscle strength, and endurance when compared with young participants. These results paralleled findings in aged mice, with significant loss of muscle mass across multiple hindlimb muscles. Ultrastructural analysis revealed substantial age-related changes in mitochondrial morphology, including decreased volume, surface area, and branching index, as well as a shift toward smaller, more fragmented, and spherical mitochondria. These structural changes likely impair oxidative capacity and drive a feed-forward cycle of mitochondrial dysfunction and ISR activation. Our findings indicate that ATF4 coordinates transcriptomic and structural adaptations in aging muscle, identifying the ISR pathway as a potential therapeutic target for preserving muscle function in older adults.

DOI: https://doi.org/10.64898/2026.03.27.711928
Trends Cancer. 2026 Apr 01. pii: S2405-8033(26)00056-7. [Epub ahead of print]

Unexpected role of the integrated stress response in cancer immune evasion.

Lucia Borriello, Lorenzo Galluzzi.

  Viral mimicry, i.e., the ability of uninfected cancer cells to emit molecular signals normally associated with infection, is paramount for anticancer immunity. Recent findings from Bossowski et al. indicate that the integrated stress response (a crucial component of cellular responses against infection) can unexpectedly promote immune evasion via an LCN2-driven, macrophage-dependent mechanism.

Keywords:  ATF4; ER stress response; SLC22A17; T cell exclusion; immunogenic cell death; three Cs

DOI:  https://doi.org/10.1016/j.trecan.2026.03.001
Front Biosci (Landmark Ed). 2026 Mar 19. 31(3): 49714

NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.

George B Stefano.

  Alzheimer's disease (AD) is increasingly associated with mitochondrial dysfunction and disrupted metabolism. Thus, the maintenance of nicotinamide adenine dinucleotide (NAD+) homeostasis is proposed as a potential therapeutic strategy. Toward this end, we suggest that AD-related mitochondrial dysfunction might be viewed as a regulatable, redox-dependent vulnerability rather than an inherently degenerative and irreversible process. This perspective advances an evolutionary model in which NAD+-mediated redox systems represent a conserved regulatory axis, and that destabilization of this axis during aging may increase susceptibility to degeneration. Here, we assess the potential of a therapeutic approach that combines this understanding of mitochondrial energy metabolism with results from preclinical studies demonstrating the impact of pharmacologic correction of NAD+ homeostasis (e.g., P7C3-A20) as contextual motivation. We explicitly elevate redox balance, rather than absolute NAD+ abundance, as the mechanistically dominant variable that shapes mitochondrial resilience, inflammatory tone, and neurovascular stability. Accordingly, the key unresolved issue is whether specific physiologic benefits might accrue from increased NAD+ availability per se or rather, the restoration of the NAD+/NADH redox ratio, with important implications for the interpretation of the results of directed metabolic interventions. Within this framework, metabolic failure in AD can be understood as an upstream permissive condition that explains, rather than replaces, canonical amyloid-β and tau-associated pathologies. While extended human lifespan may expose late-life vulnerabilities in otherwise conserved metabolic systems, claims of causal primacy, disease reversibility, and cross-neurodegenerative generalization remain premature, underscoring the need for redox-resolved, genetic, and clinical validation.

Keywords:  Alzheimer’s disease; cognition; evolution; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammatory diseases; nicotinamide adenine dinucleotide

DOI:  https://doi.org/10.31083/FBL49714
Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2508286123

Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.

Esther García-Domínguez, Cristina García-Domínguez, José Luis Cabrera-Alarcón, María Del Mar Muñoz-Hernández, Pablo Hernansanz-Agustín, Andrea Curtabbi, Julio Domenech-Fernandez, Enrique Calvo, Jesús Vázquez, Antonio L Serrano, Pura Muñoz-Cánoves, Gloria Olaso-González, José Antonio Enríquez, María Carmen Gómez-Cabrera.

  Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.

Keywords:  frailty; health span; mitochondrial function; proteomics; sarcopenia

DOI:  https://doi.org/10.1073/pnas.2508286123
Sci Rep. 2026 Apr 02.

Identification and verification of biomarkers associated with integrated stress response in heart failure.

You Wu, You Zhou, Qiuyang Huang, Ling Sun, LiSha Zhu, Tingting He, Xiangdong Meng.



Keywords:  Biomarkers; Heart failure; Immune infiltration; Integrated stress response; Nomogram construction

DOI:  https://doi.org/10.1038/s41598-026-46303-5
Cytokine. 2026 Mar 27. pii: S1043-4666(26)00038-4. [Epub ahead of print]202 157143

The IGF-1 senescence switch: a biphasic model for SASP-driven aging and precision senomodulation.

Emad Manni, Hayder M Al-Kuraishy, Nawar R Hussain, Ahmed M Abdelaziz, Gaber El-Saber Batiha.

  Insulin-like growth factor-1 (IGF-1) signaling plays a paradoxical role in aging, acting as both a mediator of tissue repair and a driver of chronic inflammation through the senescence-associated secretory phenotype (SASP). In this review, we propose a biphasic senescence switch model in which the temporal pattern of IGF-1 exposure, acute versus chronic, determines cellular fate. Transient IGF-1 signaling supports homeostasis and repair, whereas sustained activation promotes stable senescence via reactive oxygen species (ROS)-mediated DNA damage, p53/p21 pathway activation, and a potent pro-inflammatory SASP. Central to this process is IGF-binding protein-5 (IGFBP-5), which amplifies senescence in vascular and stromal cells by linking coagulation and inflammatory signals to p53-dependent arrest. The contrasting human conditions of IGF-1 deficiency (Laron syndrome) and excess (acromegaly) illustrate the lifespan and disease risks associated with dysregulated IGF-1 signaling. Emerging evidence highlights the role of extracellular vesicles in bypassing soluble IGFBP regulation, enabling paracrine propagation of senescence even under systemic IGF-1 modulation. Ultimately, we position the IGF-1/IGFBP axis as a prime target for precision senomodulation, advocating for combined strategies that temporally tune endocrine signaling with senolytic and senomorphic therapies to mitigate chronic inflammation, delay age-related dysfunction, and extend healthspan.

Keywords:  Aging; Cellular senescence; Cytokines; IGF-1; IGFBP-5; Inflammation; SASP; Senotherapeutics

DOI:  https://doi.org/10.1016/j.cyto.2026.157143
Biochem Biophys Res Commun. 2026 Mar 20. pii: S0006-291X(26)00417-1. [Epub ahead of print]816 153653

Mesenchymal stromal cells and their derivatives: A regenerative frontier in burn wound healing.

Shweta Verma, Raghavendra Upadhya, Samatha Bhat, Raviraja Neelavar Seetharam.

  Burn wounds represent complex therapeutic challenges that conventional treatments often fail to address effectively, particularly regarding prolonged healing times, excessive scarring, and recurrent infections. Mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic agent with unique regenerative capabilities specifically suited to burn wound repair through their multifaceted mechanisms, including regenerative, migratory, immunomodulatory, angiogenic, anti-fibrotic, and immunosuppressive potential. The therapeutic efficacy of MSCs is primarily mediated by their secretome, a complex mixture of bioactive factors, growth factors, and extracellular vesicles that orchestrate tissue repair processes. MSC-derived EVs have gained particular attention as cell-free therapeutic alternatives that deliver functional biomolecules while circumventing the limitations associated with direct cell transplantation. This review critically analyzes the specific and irreplaceable roles of MSCs and their derivatives in burn wound healing, focusing on their unique mechanisms of action, therapeutic advantages over conventional approaches, and the molecular pathways that distinguish them as essential therapeutic tools. We examine current evidence demonstrating their superior efficacy in promoting wound closure, reducing scar formation, and accelerating functional tissue regeneration, while identifying key research gaps and challenges that must be addressed for successful clinical translation.

Keywords:  Burns; Extracellular vesicles; Mesenchymal stromal cells; Regenerative medicine; Secretome

DOI:  https://doi.org/10.1016/j.bbrc.2026.153653
Histol Histopathol. 2026 Apr 01. 25071

Telocytes in skeletal muscle: Emerging players in homeostasis and repair/regeneration.

Irene Rosa, Eloisa Romano, Mirko Manetti.

Telocytes (TCs) have recently emerged as novel components of the skeletal muscle interstitium. They are distinguished from other stromal cells by their immunophenotypic profiles and, especially, unique ultrastructural traits. Specifically, TCs feature a small cell body and very long, thin telopodes with a moniliform appearance conferred by the alternation of slender segments (podomers) and small dilated portions (podoms). Experimental evidence suggests that, as part of the skeletal muscle stem cell niche, TCs may be involved in orchestrating satellite cell activation and myogenic differentiation through both direct physical interactions and paracrine signaling. Yet, further in-depth research is needed to uncover specific immunophenotypic signatures for skeletal muscle TCs within the niche, as well as to identify the signaling pathways by which they influence neighboring satellite cells and, possibly, other cellular components of the niche. In the present review, particular emphasis is placed on the putative strategic role of TCs in maintaining skeletal muscle tissue homeostasis, their involvement in muscle pathological alterations, and, most importantly, their possible role in the coordination of the regenerative response following injury. In perspective, the promising therapeutic potential of TC-based strategies to enhance skeletal muscle tissue repair/regeneration and restrain post-injury fibrosis is also discussed.

DOI: https://doi.org/10.14670/HH-25-071
Trends Endocrinol Metab. 2026 Mar 31. pii: S1043-2760(26)00046-9. [Epub ahead of print]

Reprogramming the mitochondrial-circadian energy code with incretins.

Enzo Nisoli, Maurizio Ragni, Chiara Ruocco, Alessandra Valerio.

  Mitochondrial dysfunction, circadian disruption, and the accumulation of senescent cells converge to impair metabolic flexibility, a unifying phenotype of obesity and aging. We frame obesity as a nutrient-driven and aging as a time-driven expression of a disrupted mitochondrial-circadian energy code, with shared outputs: impaired substrate switching and flattened energy rhythms. This opinion argues that restoring code integrity, indexed clinically by gains in metabolic flexibility, should guide therapy. Beyond appetite and glycemia, GLP-1 (glucagon-like peptide-1) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) agonists may enhance mitochondrial efficiency, support circadian alignment, and temper prosenescent signaling across target tissues (muscle, liver, adipose, islets, and brain). We outline how node-specific and combination strategies (senolytics/senomorphics, mitophagy/NAD+ support, and chrono-entrainment) could reprogram systemic energy coordination, improve durability of response, and delay age-related metabolic decline.

Keywords:  GLP-1 receptor agonists; GLP-1/GIP dual agonists; circadian rhythms; metabolic flexibility; mitochondrial dysfunction; senescence

DOI:  https://doi.org/10.1016/j.tem.2026.02.011
Nat Aging. 2026 Apr 03.

The case for space as a model of accelerated aging.

Max Manwaring-Mueller, Huixun Du, Taylor R Valentino, Matias Fuentealba, Alexander Chebykin, Fei Wu, David Furman, Daniel A Winer.

Aging is a complex biological and societal challenge, where modest advances can yield substantial clinical and economic benefits. While model organisms have uncovered key mechanisms of aging, their physiological relevance to humans remains limited. Astronauts offer a uniquely informative human model: despite being healthy and highly selected, they exhibit many hallmarks of aging and experience comparable declines in cardiovascular, musculoskeletal, cognitive and immune function-often on accelerated timelines. These changes are largely driven by four core exposures of the space environment: microgravity, circadian disruption, ionizing radiation and social isolation. Here, by tracing how environmental factors affect biological processes such as mitochondrial dysfunction, altered cytoskeletal dynamics, chronic inflammation and other canonical hallmarks of aging, we position spaceflight as a powerful model for human aging-one that unites environmental stress biology, multi-omic systems approaches and clinical research to advance both astronaut health and the healthspan of aging populations on Earth.

DOI: https://doi.org/10.1038/s43587-026-01105-2