The Mitochondrial Free Radical Theory of Aging

Aubrey de Grey ag24 at
Wed Nov 3 08:56:07 EST 1999

David Lloyd-Jones wrote:

> how in the hell does a 212 page book come to cost $89.00?

Small print run -- my publisher normally specialises in more esoteric

Lou Pagnucco wrote:

> Could you post the table of contents and a few highlights?

Here's an abbreviated table of contents that I hope gives a feel for
the highlights.

1. Introduction
1.1. What is aging?
1.2. Subjectivity and vocabulary
1.3. Why suspect mitochondria or free radicals?
1.4. Tests, interventions and consequences
2. An introduction to mitochondria
2.1. The evolutionary origins of mitochondria
2.2. Mitochondrial location and structure
2.3. Mitochondrial function
2.4. Mitochondrial DNA, or mtDNA
3. An introduction to free radicals
4. An introduction to lipid metabolism
5. A descriptive introduction to human aging
6. History of the mitochondrial free radical theory of aging, 1954-1995 
7. The status of gerontological theory in 1995 
7.1. What is a "theory of aging"?
7.2. What causes what?
7.3. The two big mechanistic gaps in MiFRA'95
7.4. Some other theories and their difficulties
8. The search for how mutant mtDNA is amplified
9. The search for how so few anaerobic cells cause so much oxidative stress
9.1. How few?
9.2. The creation of mtDNA-less human cell lines
9.3. The plasma membrane oxidoreductase
9.4. Getting the most ATP without oxygen
9.5. PMOR: the solution, or the problem?
9.6. Systemic consequences: the "reductive hotspot hypothesis"
9.7. Alternative pathways
10. Frequently-asked questions
10.1. Why is Carl Lewis still alive?
10.2. Why haven't we evolved our mitochondrial DNA away?
10.3. How does the germ line avoid mtDNA decay?
10.4. Why aren't dietary antioxidants more beneficial?
10.5. Why hasn't SOS been tested in flies or worms?
10.6. How can mutant mitochondria survive, let alone out-compete working ones?
10.7. Why doesn't the polyploidy of mitochondria protect them? 
10.8. What about mitochondrial fusion?
10.9. Why doesn't the body just let (or make) affected cells die?
10.10. What about in situ membrane repair?
10.11. How can SOS explain mtDNA depletion?
10.12. Why isn't longevity mainly maternally inherited?
10.13. Why don't plasma antioxidants totally prevent LDL oxidation?   
10.14. Why doesn't low plasma LDL retard aging?
10.15. Isn't this "reductive hotspot" business all rather far-fetched?
11. A challenge from textbook bioenergetics and free radical chemistry 
12. Some testable predictions of MiFRA
13. Prospects for intervention
13.1. Some probably futile approaches
13.2. A way to obviate mtDNA
13.3. A way to destroy anaerobic cells
13.4. Gene therapy
14. Ablation of anaerobic cells: techniques and hurdles
15. Transgenic copies of mtDNA: techniques and hurdles
16. Prospective impact on the healthy human lifespan
16.1. Plausibility of engineered negligible senescence
16.2. Is MiFRA a theory of aging? 
17. Conclusion; the role of the gerontologist today
17.1. Demographic challenges
17.2. Accidents, diseases and lifestyle
17.3. An operational definition of the "defeat" of aging
17.4. Possibilities versus probabilities

Aubrey de Grey

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