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senescence

Saturday 19 July 2003

- DNA somatic mutations, poor DNA repair and aging

As cells get older, the amount of DNA damage accumulates overtaking the rate of repair and resulting in a reduction of protein synthesis.

As proteins in the cell are used for numerous vital functions, the cell becomes slowly impaired and eventually dies. When enough cells in an organ reach such a state, the organ itself will become compromised and the symptoms of disease begin to manifest.

Experimental studies in animals, where genes associated with DNA repair were silenced, resulted in accelerated aging, early manifestation of age related diseases and increased susceptibility to cancer.

In studies where the expression of certain DNA repair genes was increased resulted in extended lifespan and resistance to carcinogenic agents in cultured cells.

- Longevity genes and DNA repair

Most lifespan influencing genes affect the rate of DNA damageCertain genes are known to influence variation in lifespan within a population of organisms. Studies in model organisms such as yeast, worms, flies and mice have identified single genes, which when modified, can double lifespan (eg. a mutation in the age-1 gene of the nematode Caenorhabditis elegans).

These genes are known to be associated specifically with cell functions other than DNA repair, but when the pathways that they influence are followed to their final destination, it was observed that they mediate one of three functions: increasing the rate of DNA repair, increasing the rate of antioxidant production, or decreasing the rate of oxidant production.

Therefore, the common pattern across most lifespan influencing genes is in their downstream effect of altering the rate of DNA damage.

- Caloric restriction increases DNA repair

Caloric restriction (CR) has been shown to increase lifespan and decrease age related disease in all organisms where it has been studied, from single celled life such as yeast, to multicellular organisms such as worms, flies, mice and primates.

The mechanism by which CR works is associated with a number of genes related to nutrient sensing which signal the cell to alter metabolic activity when there is a shortage of nutrients, particularly carbohydrates.

When the cell senses a decrease in carbohydrate availability, activation of the lifespan influencing genes DAF-2, AGE-1 and SIR-2 is triggered.

The reason why a shortage of nutrients will induce in a cell a state of increased DNA repair and an increase in lifespan is suggested to be associated with an evolutionarily conserved mechanism of cellular hibernation.

Essentially this permits a cell to maintain a dormant state until conditions that are more favorable are met. During this period, the cell must decrease its normal rate of metabolism and one of the ways it can accomplish this is by reducing genomic instability.

Thus, the cellular rate of aging is mutable and can be influenced by environmental factors such as nutrient availability, which mediate their effect by altering the rate of DNA repair.

- oxydative stress
- energy and caloric consomption
- mitochondrial DNA mutations

- proteasome

  • See Carrard G, et al: Impairment of proteasome structure and function in aging. Int J Biochem Cell Biol 34:1461, 2002.

References

- Fraga MF, Esteller M. Epigenetics and aging: the targets and the marks. Trends Genet. 2007 Aug;23(8):413-8. PMID: 17559965

- Bishop NA, Guarente L. Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet. 2007 Nov;8(11):835-44. PMID: 17909538

- Russell SJ, Kahn CR. Endocrine regulation of ageing. Nat Rev Mol Cell Biol. 2007 Sep;8(9):681-91. PMID: 17684529

- Oberdoerffer P, Sinclair DA. The role of nuclear architecture in genomic instability and ageing. Nat Rev Mol Cell Biol. 2007 Sep;8(9):692-702. PMID: 17700626

- Christensen K, Johnson TE, Vaupel JW. The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet. 2006 Jun;7(6):436-48. PMID: 16708071

- Finkel T. Opinion: Radical medicine: treating ageing to cure disease. Nat Rev Mol Cell Biol. 2005 Dec;6(12):971-6. PMID: 16227974

- Balducci L, Ershler WB. Cancer and ageing: a nexus at several levels. Nat Rev Cancer. 2005 Aug;5(8):655-62. PMID: 16056261

- Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 2005 Aug;6(8):611-22. PMID: 16136653

- Longo VD, Mitteldorf J, Skulachev VP. Opinion: programmed and altruistic ageing. Nat Rev Genet. 2005 Nov;6(11):866-72. PMID: 16304601

- Chang S. Modeling premature aging syndromes with the telomerase knockout mouse. Curr Mol Med. 2005 Mar;5(2):153-8. PMID: 15974868

- Mounkes LC, Stewart CL. Aging and nuclear organization: lamins and progeria. Curr Opin Cell Biol. 2004 Jun;16(3):322-7. PMID: 15145358

- Kirkwood TB. Genes that shape the course of ageing. Trends Endocrinol Metab. 2003 Oct;14(8):345-7. PMID: 14516929

- Purdom S, Chen QM. p66(Shc): at the crossroad of oxidative stress and the genetics of aging. Trends Mol Med. 2003 May;9(5):206-10. PMID: 12763525

- Campisi J. Related Articles, Links ageing: rival demons? Nat Rev Cancer. 2003 May;3(5):339-49. PMID: 12724732

- Schmitt CA. Senescence, apoptosis and therapy—cutting the lifelines of cancer. Nat Rev Cancer. 2003 Apr;3(4):286-95. PMID: 12671667

- Carrard G, et al: Impairment of proteasome structure and function in aging. Int J Biochem Cell Biol 34:1461, 2002.

- Partridge L, Gems D. Mechanisms of ageing: public or private? Nat Rev Genet. 2002 Mar;3(3):165-75. PMID: 11972154

- Helfand SL, Inouye SK. Rejuvenating views of the ageing process. Nat Rev Genet. 2002 Feb;3(2):149-53. PMID: 11836509

- Campisi J. Cancer and ageing: rival demons? Nat Rev Cancer. 2003 May;3(5):339-49. PMID: 12724732

- Kuro-o M. Disease model: human aging. Trends Mol Med. 2001 Apr;7(4):179-81. PMID: 11286943

- Jazwinski SM. Metabolic control and ageing. Trends Genet. 2000 Nov;16(11):506-11. PMID: 11074293

- Marciniak RA, Johnson FB, Guarente L. Dyskeratosis congenita, telomeres and human ageing. Trends Genet. 2000 May;16(5):193-5. PMID: 10782108

- Vijg J. Somatic mutations and aging: a re-evaluation. Mutat Res. 2000 Jan 17;447(1):117-35. PMID: 10686308

- Lightowlers RN, Jacobs HT, Kajander OA. Mitochondrial DNA—all things bad? Trends Genet. 1999 Mar;15(3):91-3. PMID: 10203801

- Guarente L, Kenyon C: Genetic pathways that regulate ageing in model organisms. Nature 408:255, 2000.

- Finkel T, Holbrook NJ: Oxidants, oxidative stress, and the biology of ageing. Nature 408:239, 2000.

- Gilchrest BA, Bohr VA: Aging processes, DNA damage, and repair. FASEB J 11:322, 1997.