Path 6: Mitochondrial Dysfunction & Oxidative Stress

Rationale: Powerhouse failure: the free radical theory lives on. This path centers on mitochondria, the organelles that produce ATP and generate reactive oxygen species (ROS) as byproducts. Harman’s free radical theory proposed that cumulative oxidative damage by ROS is a primary cause of aging. mtDNA is especially prone to mutations from ROS. If aging is largely caused by oxidative damage, boosting antioxidant defenses or improving mitochondrial function should slow aging.

Prerequisites: Bioenergetics (Krebs cycle, electron transport), redox biology, physiology.

Dependencies: Connects to Path 2 (genomic instability) because mtDNA mutations accumulate, to Path 5 (proteostasis) because oxidized proteins must be cleared, and Path 7 (nutrient sensing) as metabolic rate and mitochondrial output are linked.

Signs of Progress: Interventions that improve mitochondrial function in aged organisms and yield longer life. Successful replacement or repair of mitochondrial DNA. Developing methods to replenish mitochondria via mitophagy induction or mitochondrial transplantation.

BC6.1: Mitochondrial Biology & ROS

Scope: How mitochondria produce energy via oxidative phosphorylation and how ROS are generated. mtDNA specifics.

• Nicholls, D.G. & Ferguson, S. Bioenergetics 4. Academic Press, 2013. – Student-friendly introduction to ETC and superoxide formation.
• Brand, Martin D. “The sites and topology of mitochondrial superoxide production.” Exp. Gerontol., 2010. – Maps exactly where in mitochondria ROS come from.
• Balaban, R.S., Nemoto, S. & Finkel, T. “Mitochondria, oxidants, and aging.” Cell, 2005. – Classic review connecting mitochondria to aging.

BC6.2: Mitochondrial DNA Mutations in Aging

Scope: Evidence that mtDNA mutations accumulate with age and can cause aging phenotypes. The PolgA mutator mouse.

• Trifunovic, A. et al. “Premature aging in mice expressing defective mitochondrial DNA polymerase.” Nature, 2004. – The mutator mouse paper: lots of mtDNA mutations = premature aging.
• Bratic, I. & Larsson, N.-G. “The role of mitochondria in aging.” J. Clin. Invest., 2013. – Covers the mutator mouse and other evidence.
• Khrapko, K. & Vijg, J. “Mitochondrial DNA mutations and aging: devils in the details?” Trends Genet., 2009. – Balanced take on whether mtDNA mutations drive aging.

BC6.3: Oxidative Damage and Antioxidant Experiments

Scope: Experiments modulating oxidative stress. Mixed results for antioxidant supplements; mitohormesis concept.

• Salmon, Adam B. et al. “Transgenic mice expressing mitochondrial catalase age normally.” Proc. Natl. Acad. Sci. USA, 2010. – Contradicted earlier data, showing no lifespan extension with mito-catalase.
• Li, Y. et al. “Catalase overexpression in mice prevents cataracts and cardiac aging, but fails to extend lifespan.” Free Radic. Biol. Med., 2009. – Tissue-specific benefits but not overall lifespan.
• Ristow, M. & Schmeisser, S. “Extending life span by increasing oxidative stress.” Free Radic. Biol. Med., 2011. – Provocative review arguing low-level oxidative stress triggers beneficial responses (mitohormesis).

BC6.4: Mitophagy and Mitochondrial Quality Control

Scope: How cells deal with defective mitochondria via mitophagy (PINK1/Parkin pathway). Fission/fusion dynamics.

• Palikaras, K. et al. “Mechanisms of mitophagy in cellular homeostasis, physiology and pathology.” Nat. Cell Biol., 2018. – Comprehensive review with sections on aging.
• Lopez-Otin, C. et al. “The mitochondrial unfolded protein response and longevity.” Trends Cell Biol., 2016. – Mild mitochondrial stress induces protective UPR^mt^ increasing lifespan.
• Sun, N. et al. “Measuring in vivo mitophagy.” Mol. Cell, 2015. – Developed a mitophagy reporter in mice, showing how mitophagy changes with age.

BC6.5: Therapies Targeting Mitochondria

Scope: Mitochondria-targeted antioxidants, NAD+ boosters, exercise/diet, mitochondrial replacement, gene therapy.

• Khushmitdinov, A. et al. “Mitochondria-targeted antioxidant SkQ1 delays senescence.” Aging (Albany NY), 2014. – Effects of SkQ1 on cells/animals.
• Yen, K. et al. “The emerging role of the mitochondrial-derived peptide humanin in stress resistance.” J. Mol. Endocrinol., 2013. – Small peptides encoded in mtDNA with protective effects.
• Gonzalez-Freire, M. et al. “Reconsidering the role of mitochondria in aging.” J. Gerontol. A, 2015. – Holistic look: exercise, CR, mitochondrial metabolites controlling epigenetics.

Bibliography (Path 6)

• Bratic, I. & Nils-Göran Larsson. “The Role of Mitochondria in Aging.” J. Clin. Invest. 123(3): 951–957, 2013. (Evidence linking mtDNA mutations to aging)
• Sun, Nan et al. “The Mitochondrial Basis of Aging.” Mol. Cell 61(5): 654–666, 2016. (Mitochondrial function decline and pathways like mitophagy)
• Beckman, Kenneth B. & Bruce N. Ames. “The Free Radical Theory of Aging Matures.” Physiol. Rev. 78(2): 547–581, 1998. (Classic comprehensive review, though some conclusions revised)
• López-Lluch, Guillermo & Plácido Navas. “Calorie Restriction as an Intervention in Ageing.” J. Physiol. 594(8): 2043–2060, 2016. (CR changes mitochondrial function and ROS production)
• Ristow, Michael & Kathrin Schmeisser. “Extending Life Span by Increasing Oxidative Stress.” Free Radic. Biol. Med. 51(2): 327–336, 2011. (Mitohormesis: increased ROS via exercise/CR leads to adaptive stress responses)