The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
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The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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192 The Mitochondrial Free Radical Theory of Aging Statement 4 is essentially a one-sentence summary of Chapter 5. The major classes of deleterious, late-onset macroscopic change in the human body, which were enumerated and described there, are all maintenance failures. At first glance this is virtually a truism, since maintenance is simply the avoidance of degradative changes; after maturity (or, in women, menopause), all changes are degradative and are reasonably classified as aspects of aging. In fact it is not quite so simple, because the abolition of a decline in the quality of maintenance is not equivalent to abolition of damage, only to abolition of acceleration of that damage. Thus, with permanently youthful maintenance processes we would still age, but at a constant, rather than accelerating, rate. That is quite sufficient, however, to justify statement 4, since the degree of acceleration of aging over a lifetime is very substantial. Only statement 2 is somewhat less well supported, as yet. It seems highly likely that the process described in Section 9.6 (haemin-driven oxidation of LDL components, which promote further chain reactions after import) occurs to some extent, since all the component steps are chemically favoured. But the only evidence that this process (together with parallel ones also initiated by the PMOR of anaerobic cells) is the main source of oxidative stress is negative: that there seems to be no other process to account for it. Inside a mitochondrially healthy cell, the only macroscopic irreversible change (in the sense defined in Section 5.6) that occurs with time is the accumulation in lysosomes of lipofuscin, a fluorescent concoction of protein, lipids and iron atoms which is popularly known as “age pigment.” But it is unclear how lipofuscin can be doing cells any harm at all (except in the extreme case of the aged retina: see Section 5.4), since it is packaged up in lysosomes. It is thus very hard to blame lipofuscin for oxidative stress (though not completely unreasonable: Brunk has suggested 14,15 that it causes problems passively, by attracting the futile attentions of hydrolytic enzymes, which are thereby in shorter supply to digest newly-phagocytosed material). Similarly, no other extracellular mediator of oxidative stress has been convincingly proposed. Some antioxidant hormones decline in activity with age, but their supplementation seems to confer no great benefit, suggesting that they are only peripherally involved. Finally, insofar as there remains doubt that anaerobic cells are the main source of oxidative stress, one must recall that there is no shortage of available tests, as was discussed in Section 12.2. In summary, then, there appears to be a significant possibility that the theory presented here is correct in the strong sense defined in Section 7.1, namely that complete abolition of the effects of somatic mtDNA mutations would slow all other aspects of aging by at least a factor of two. References 1. Holliday R. Understanding ageing. Cambridge: Cambridge University Press, 1995. 2. Wilson BS, Finley CC, Lawson DT et al. Better speech recognition with cochlear implants. Nature 1991; 352:236-238. 3. Kirschenbaum B, Nedergaard M, Preuss A et al. In vitro neuronal production and differentiation by precursor cells derived from the adult human forebrain. Cereb Cortex 1994; 4:576-589. 4. Goldman SA, Nedergaard M, Crystal RG et al. Neural precursors and neuronal production in the adult mammalian forebrain. Ann NY Acad Sci 1997; 835:30-55. 5. Brustle O, McKay RD. Neuronal progenitors as tools for cell replacement in the nervous system. Curr Opin Neurobiol 1996; 6:688-695. 6. a)Pincus DW, Goodman RR, Fraser RAR et al. Neural stem and progenitor cells: A strategy for gene therapy and brain repair. Neurosurgery 1998; 42:858-867. 6. b)Lowenstein DH, Parent JM. Brain, heal thyself. Science 1999; 283:1126-1127. 7. Hibbard E. Visual recovery following regeneration of the optic nerve through the oculomotor nerve root in Xenopus. Exp Neurol 1967; 19:350-356.

Prospective Impact on the Healthy Human Lifespan 8. Muneoka K, Bryant SV. Evidence that patterning mechanisms in developing and regenerating limbs are the same. Nature 1982; 298:369-371. 9. Brockes JP. Amphibian limb regeneration: Rebuilding a complex structure. Science 1997; 276:81-87. 10. Borgens RB. Mice regrow the tips of their foretoes. Science 1982; 217:747-750. 11. Illingworth CM. Trapped fingers and amputated finger tips in children. J Pediatr Surg 1974; 9:853-858. 12. Jackson AL, Loeb LA. The mutation rate and cancer. Genetics 1998; 148:1483-1490. 13. Ono T, Cutler RG. Age-dependent relaxation of gene repression: Increase of endogenous murine leukemia virus-related and globin-related RNA in brain and liver of mice. Proc Natl Acad Sci USA 1978; 75:4431-4435. 14. Brunk UT, Jones CB, Sohal RS. A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis. Mutat Res 1992; 275:395-403. 15. Brunk UT, Terman A. The mitochondrial-lysosomal axis theory of cellular aging. In: Cadenas E, Packer L, eds. Understanding the basis of aging: Mitochondria, oxidants and aging. New York: Marcel Dekker, Inc., 1997:229-250. 193

Prospective Impact on the Healthy Human Lifespan<br />

8. Muneoka K, Bryant SV. Evidence that patterning mechanisms in developing and<br />

regenerating limbs are the same. Nature 1982; 298:369-371.<br />

9. Brockes JP. Amphibian limb regeneration: Rebuilding a complex structure. Science 1997;<br />

276:81-87.<br />

10. Borgens RB. Mice regrow the tips <strong>of</strong> their foretoes. Science 1982; 217:747-750.<br />

11. Illingworth CM. Trapped fingers and amputated finger tips in children. J Pediatr Surg<br />

1974; 9:853-858.<br />

12. Jackson AL, Loeb LA. <strong>The</strong> mutation rate and cancer. Genetics 1998; 148:1483-1490.<br />

13. Ono T, Cutler RG. Age-dependent relaxation <strong>of</strong> gene repression: Increase <strong>of</strong> endogenous<br />

murine leukemia virus-related and globin-related RNA in brain and liver <strong>of</strong> mice. Proc<br />

Natl Acad Sci USA 1978; 75:4431-4435.<br />

14. Brunk UT, Jones CB, Sohal RS. A novel hypothesis <strong>of</strong> lip<strong>of</strong>uscinogenesis and cellular aging<br />

based on interactions between oxidative stress and autophagocytosis. Mutat Res 1992;<br />

275:395-403.<br />

15. Brunk UT, Terman A. <strong>The</strong> mitochondrial-lysosomal axis theory <strong>of</strong> cellular aging.<br />

In: Cadenas E, Packer L, eds. Understanding the basis <strong>of</strong> aging: Mitochondria, oxidants<br />

and aging. New York: Marcel Dekker, Inc., 1997:229-250.<br />

193

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