Ageing works like this:
1) Electrons leak from mitochondrial Complexes I & III forming superoxide anion.
2) The increasing rate of leakage and the further breakdown of mitochondrial components with time under the superoxide (...and peroxynitrite & peroxide) onslaught is strongly determined by genetically controlled factors: i.e., the structure of mitochondrial proteins and membranes. Hence leakage is species-specific. The net effect is that leakage is a mostly monotonically increasing function of time.
3) While the charged Superoxide Anion does not escape to the cytoplasm easily from the mitochondrial outer membrane...
4) Mitochondrial Superoxide Dismutase (SOD) converts Superoxide Anion into Hydrogen Peroxide.
5) H2O2 is neutral and easily diffuses through the mitochondrial outer membrane, entering the cytoplasm.
6) In the cytoplasm, peroxide prompts protein kinase C variants (incl.epsilon) to upregulate cytoplasmic NOX. NOX outputs O2-; and eventually via cytoplasmic SOD, H2O2; acting as a high-gain peroxide amplifier. THIS IS AGE-LINKED, ENDOGENOUS CHRONIC OXIDATIVE STRESS.
7) H2O2 is an important signalling molecule in stress signal transduction; such transduction is ramped up.
The MAPK/ERK cascade is overactivated.
The key stress transcription factors NF-kappaB; AP1 etc are constitutively upregulated.
Angiotensin2 is upregulated. The PI3K-Akt signalling cascade is chronically activated.
The transcription factors FOXO3A (and other FOXOs) are phosphorylated by Akt and translocated from the nucleus.
Bad is similarly phosphorylated. mTOR is 'non-phosphorylatively' activated by Akt.
Note that FOXOs, Bad, mTOR are downstream of PI3K. SIRT1 & klotho are upstream.
8) These factors upregulate the transcription of cytokines and a whole range of stress molecules; unleash a chronic cytokine onslaught on the cell & tissues. A number of runaway positive feedback loop including TLRs and RAGE is ensured.
9) Under the signalling from the transcribed products, massive tissue remodelling and physiological change at the cell, tissue system & organism level is enforced. Both Hypertrophic & Degenerative signalling abound.
10) ...and checkpoints are disabled promoting oncogenesis;apoptosis is aberrant
11) ...and stem cell niche failure - either through complete abrogation; or through enforced quiescence is the norm.
12) ...and mitochondrial biogeneisis is abrogated, OXPHOS is downregulated
13)...and cell senescence is upregulated, in part through p38MAPK