- mitochondria-targeted catalase overexpression increases mouse lifespan (15-20% median increase) and reduces age-associated oxidative damage.
- Mclk1/Coq7 haploinsufficiency (Mclk1 +/-): decreasing ubiquinone-biosynthesis enzyme activity produces long-lived mice across backgrounds; mechanisms include altered mitochondrial ROS/signaling with preserved respiration.
- SURF1 knockout
- hMTH1/NUDT1 overexpression clears 8-oxo-dGTP from the nucleotide pool, lowers oxidative nucleic-acid damage, and extends lifespan.
- OPA1 overexpression (inner-membrane fusion/cristae integrity) preserves cristae architecture, improves respiratory-chain efficiency.
- ATG5 overexpression to increase mitophagy increases mouse lifespan.
- Parkin (PARK2) overexpression for more mitophagy.
- mtOGG1 (mitochondria-targeted 8-oxoguanine DNA glycosylase) overexpression to improve mtDNA base-excision repair.
- PRDX3 (mitochondrial peroxiredoxin) overexpression to lower mitochonrial H2O2 (? unclear if this is effective)
mitochondrion membrane "peroxidizability" is lower in long-lived species. Across mammals (incl. humans) and birds, mitochondrial phospholipids have fewer highly polyunsaturated fatty acids (esp. DHA) → membranes are harder to oxidize, lipid peroxidation is lower, and mitochondria age more slowly. Humans fall on the "low peroxidizability" end vs mice. Naked mole-rats and many birds are extreme examples
mtDNA mutations scale with lifespan. get good at mtDNA repair or mitophagy.
antioxidant/repair capacity or location may track longevity better than raw ROS production. (ref)
bats have enhanced mitophagy/DNA-damage responses and a dampened NLRP3 inflammasome, reducing mito-inflammation during stress (flight). (ref)
human mitochondria have lower PUFA content and a lower peroxidation index than mice.
naked mole rats mitochondrial membranes are unusually resistant to peroxidation (very low DHA in phospholipids).
human oocyte mitochondria seem to be uniquely protected. (ref)
TODO: look for human mitochondrial longevity mutations in the literature.
mtDNA copy number (mtDNA-CN) should be increased (ref)
MitoSENS: mitochondria DNA mutations need to be bypassed (MitoSENS) by moving mtDNA genes to the nucleus (allotopic expression) and import the proteins back into mitochondria to maintain cellular respiration. Allotopic expression of mitochondrial genes into the nucleus will require recoding for cytosolic translation and also mitochondrial targeting sequences. Mitochondrial-targeted nucleases could be used to eliminate mutant genomes. Therapeutic mitochondrial transplantation or progenitor cell transfer. Engineer enhanced mitochondrial import machinery. Add mitochondrial-targeted DNA repair systems. Overexpress mitochondrial biogenesis factors (PGC-1α, NRF1/2).
See also mitochondria.