Mitochondrial dysfunction and aging: multidimensional mechanisms and

#1

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.

O3:

TL;DR — Wei et al. (Biogerontology, 9 July 2025) review how mitochondrial dysfunction drives ageing through five, mutually connected axes: (1) metabolic reprogramming (PI3K/AKT/mTOR hyperactivation, AMPK/SIRT1/PGC‑1α suppression), (2) epigenetic regulation, (3) telomere damage (p53–PGC‑1α axis), (4) autophagy/mitophagy imbalance, and (5) the SASP via cGAS–STING–NF‑ÎșB. They argue for multi‑omics mapping of mitochondria–other‑organelle crosstalk and propose combined interventions (e.g., metabolic reprogramming modulators + SASP inhibitors; sirtuin/AMPK activators; telomerase targeting). The piece’s main novelty is the integrative framing—positioning these pathways as a single, bidirectionally wired network and explicitly distinguishing ageing-associated metabolic reprogramming from cancer’s proliferative Warburg program. The review is comprehensive but largely synthesises known pathways, gives little quantitative or tissue/sex-specific resolution, underplays mtDNA heteroplasmy, mitochondrial peptides, fission–fusion dynamics and mitohormesis, and stays high-level on how, concretely, to execute the proposed multi‑omics/combination-therapy agenda. (SpringerLink, SpringerLink, SpringerLink)

1) Structured summary

Scope & claim

  • Ageing is framed as cellular senescence-centric, with mitochondria as a core driver that feeds into DNA damage, epigenetic drift, SASP, and impaired intercellular communication. The review’s purpose is to integrate disparate mitochondria–ageing mechanisms into a unified schema and outline therapeutic entry points. (SpringerLink)

Key mechanistic pillars

  1. Metabolic reprogramming
  • Senescent cells shift toward glycolysis (GLUT1/HK2 up, PDH complex down), with PI3K/AKT/mTOR hyperactivation and impaired OXPHOS; AMPK/SIRT1/PGC‑1α is the counter‑regulatory axis. Distinguishes tumour vs ageing metabolic reprogramming (degenerative, survival‑oriented). (SpringerLink, SpringerLink)
  1. Epigenetic regulation
  • Mitochondrial dysfunction feeds DNA methylation and histone‑modification changes, but details are mostly surveyed, not expanded experimentally. (SpringerLink)
  1. Telomere damage → mitochondrial compromise
  • p53–PGC‑1α pathway links telomere shortening to reduced mitochondrial biogenesis and ROS accumulation. (SpringerLink)
  1. Autophagy/mitophagy imbalance
  • Dual roles: quality control vs apoptosis induction; homeostasis is essential to delay ageing. AMPK promotes, mTOR suppresses, mitophagy. (SpringerLink, SpringerLink)
  1. SASP & inflammation
  • cGAS–STING and ROS→NF‑ÎșB axes connect mitochondrial stress to inflammatory SASP propagation (e.g., IL‑6). (SpringerLink, SpringerLink)

Therapeutic suggestions

  • Target nodes: Sirtuins (SIRT1/SIRT3), AMPK, telomerase, PI3K/AKT/mTOR, SASP inhibitors/senolytics.
  • Strategy: multi‑target/combination therapies (e.g., metabolic reprogramming modulators + SASP inhibition) and multi‑omics integration to map organelle crosstalk (ER, lysosome). (SpringerLink)

2) What’s (relatively) novel here?

  1. A single, explicitly interconnected framework
  • The paper treats metabolic, telomeric, epigenetic, autophagic and inflammatory routes as a bidirectionally wired network, not as siloed mechanisms—as many earlier reviews did. (SpringerLink, SpringerLink)
  1. Clearer articulation of regulatory “hubs”
  • It elevates the SIRT1/PGC‑1α and AMPK/mTOR axes as master switches that decide whether cells lock into glycolysis–lipogenesis vs restore mitochondrial homeostasis. (SpringerLink)
  1. Framing of ageing metabolic reprogramming as “degenerative survival” vs cancer’s proliferative Warburg shift—a nuance that’s often glossed over. (SpringerLink)
  2. Call for multi‑omics plus organelle‑interaction maps (mitochondria–ER–lysosome) to operationalise precision gerotherapeutics. Prior reviews mention multi‑omics, but here it’s tightly tied to the cross‑talk model. (SpringerLink)
  3. Therapeutic emphasis on combination targeting (e.g., metabolic + SASP) rather than single-pathway interventions. (SpringerLink)

3) Critique (limitations & how to improve)

Conceptual / scope

  1. Mostly a synthesis, not a genuinely new model
  • The “integration” is valuable but remains narrative—no causal/quantitative framework (e.g., network modelling, dynamic systems, or mediation analyses across omics layers). Provide testable predictions or formalised diagrams with directionality/weights. (SpringerLink, SpringerLink)
  1. Underrepresentation of key mitochondrial topics
  • mtDNA heteroplasmy, clonal expansion, replication stress, mitochondrial dynamics (DRP1/OPA1/MFN1/2), and mitochondria-derived peptides (e.g., MOTS‑c, humanin) are either missing or cursory—yet central to ageing and translational prospects. (SpringerLink)
  1. Mitohormesis & longevity paradoxes are not engaged
  • Evidence that mild mitochondrial stress/ROS can extend lifespan (e.g., in C. elegans, mice) isn’t reconciled with the “ROS → damage” narrative; this weakens therapeutic generalisations. (SpringerLink)
  1. Tissue, cell-type, and sex-specific heterogeneity is largely absent
  • The review doesn’t dissect how the highlighted hubs (e.g., AMPK/mTOR, SIRT1) behave differently in brain vs heart vs immune cells, or in males vs females—critical for precision geroscience. (SpringerLink)
  1. Clinical translation remains high-level
  • “Combine SASP inhibition with metabolic reprogramming” is plausible, but no prioritised target pairs, dosing logic, or biomarker strategies are offered (e.g., NADâș/acylcarnitines + SASP panels; mtDNAcn + DNAme clocks). (SpringerLink)
  1. Organelle crosstalk is proposed but not detailed
  • Little mechanistic depth on MAMs (mitochondria–ER contacts), lysosomal signalling (TFEB/TFE3), or peroxisomal ROS/lipid metabolism—all directly relevant to their framework. (SpringerLink)
  1. Biomarker/clock integration is superficial
  • The piece gestures to epigenetics but doesn’t integrate mitochondrial readouts (mtDNA mutations, NADâș, acyl‑CoA pools) with epigenetic clocks / proteomic clocks to form a practical stratification toolkit. (SpringerLink)
  1. No discussion of safety/adverse trade‑offs
  • Long‑term mTOR inhibition, telomerase activation, or aggressive SASP suppression have trade‑offs (tumorigenesis, impaired wound healing, immune modulation) that aren’t examined. (SpringerLink)

4) How to build on it (actionable research ideas)

  • Quantify the network: develop a dynamic, multi‑omic causal graph linking mtDNA mutations, NADâș flux, AMPK/mTOR activity, SASP cytokines, and telomere status; validate across tissues and ages.
  • Organelle-interactome atlas: map MAM density/function vs ageing phenotypes and overlay with lipidomics + single‑cell ATAC/RNA‑seq.
  • Combination trials with biomarkers: e.g., NADâș boosters or AMPK activators + senomorphic (JAK/STAT or NF‑ÎșB inhibitors), tracked by SASP panels, mitochondrial respiration (Seahorse), and DNA methylation clocks.
  • Stratify by heteroplasmy burden / mitochondrial peptides to see who benefits from which arm (metabolic vs SASP).
  • Mitohormesis window finding: titrate mitochondrial stressors (e.g., mild ETC inhibitors, exercise mimetics) to locate beneficial vs harmful ROS bands.

Bottom line

A well-organised, contemporary review that pulls multiple well-known mitochondrial–ageing mechanisms into one network narrative and argues for multi-omics + combination therapies. The incremental novelty lies in the integration and the framing, not in uncovering new mechanisms. To be more impactful, future work should quantify the proposed network, incorporate neglected mitochondrial biology (heteroplasmy, dynamics, peptides), account for heterogeneity, and specify concrete translational roadmaps. (SpringerLink, SpringerLink, SpringerLink)

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#2

My criticism is no reference to splicing. Nor any proper link between mitochondrial function and gene expression.

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#3

Methylene Blue, Mitochondrial Dysfunction and Neurodegeneration

I am using methylene blue with red light therapy to gain a little more energy and to save my aged brain. I do feel a little more energetic when I am taking methylene blue, but that might be because I have low hemoglobin.

There are many who claim, but I can find no quality supportive studies, that red light therapy and methylene blue are synergistic.

“Combined Mitochondrial Support: Methylene blue enhances mitochondrial function by facilitating electron transport, while red light therapy stimulates ATP production within the mitochondria. Both interventions increase the expression of brain cytochrome oxidase in vivo.”

Chat GPT-4o:

":brain: Conclusion

Yes, there is credible mechanistic and preclinical evidence that methylene blue and red/NIR light therapy may synergistically enhance mitochondrial function, particularly under stress or disease conditions. The combo could be a promising therapeutic strategy for neurodegeneration, fatigue, or mitochondrial dysfunction — but clinical trials are still needed."

Though at 85, I still go to the gym and recently passed a cognitive function test given to the elderly.

Methylene Blue, Mitochondrial Dysfunction and Neurodegeneration

  1. Mitochondrial Enhancement:

Methylene blue functions as a mitochondrial enhancer by facilitating electron transport along the respiratory chain, thereby promoting cellular energy production. This mitochondrial support can enhance cellular function and vitality, making it beneficial for conditions characterized by mitochondrial dysfunction.

Methylene Blue, Mitochondrial Dysfunction and Neurodegeneration

I may have posted this before. If so, I apologize.

From Mitochondrial Function to Neuroprotection – An Emerging Role for Methylene Blue

“From Mitochondrial Function to Neuroprotection – An Emerging Role for Methylene Blue - PMC”

A Novel Approach of Combining Methylene Blue Photodynamic Inactivation, Photobiomodulation and Oral Ingested Methylene Blue in COVID-19 Management: A Pilot Clinical Study with 12-Month Follow-Up

“https://www.mdpi.com/2076-3921/11/11/2211”

Modulation of mitochondrial function with near-infrared light reduces brain injury in a translational model of cardiac arrest.

“Modulation of mitochondrial function with near-infrared light reduces brain injury in a translational model of cardiac arrest | Critical Care | Full Text”

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