Stem cell theory of aging

Some of the proponents of this theory have been Norman E. Sharpless, Ronald A. DePinho, Huber Warner, Alessandro Testori [2] and others. Warner came to this conclusion after analyzing human case of Hutchinson's Gilford syndrome and mouse models of accelerated aging.

Stem cells will turn into certain cells as the body needs them. Stem cells divide more than non stem cells so the tendency of accumulating damage is greater. Although they have protective mechanisms, they still age and lose function. Matthew R. Wallenfang, Renuka Nayak and Stephen DiNardo showed this in their study. According to their findings, it is possible to track male GSCs labeled with lacZ gene in Drosophila model by inducing recombination with heat shock and observe the decrease in GSC number with aging. In order to mark GSCs with lacZ gene, flip recombinase (Flp)-mediated recombination is used to combine a ubiquitously active tubulin promoter followed by an FRT (flip recombinase target) site with a promotorless lacZ ORF (open reading frame) preceded by an FRT site. Heat shock is used to induce Flp recombinase marker gene expression is activated in dividing cells due to recombination. Consequently, all clone of cells derived from GSC are marked with a functional lacZ gene. By tracking the marked cells, they were able to show that GSCs do age.[3]

Another study in a mouse model shows that stem cells do age and their aging can lead to heart failure. Findings of the study indicate that diabetes leads to premature myocyte senescence and death and together they result in the development of cardiomyopathy due to decreased muscle mass.[4]

Recent work has suggested that, although adult tissue stem cells may the key cell type in the aging process, they may contribute via reducing their differentiation rates, rather than via becoming exhausted. Under this model, when stem cells divide but do not differentiate, they produce an excess of daughter stem cells. This phenotype will be selected for, at the cellular level, if it is caused by heritable epigenetic changes or genetic mutations, and has the potential to overwhelm homeostatic regulation of cell numbers when organismal integrity is under reduced selection in later life.[5]

Behrens et al.[6] have reviewed evidence that age-dependent accumulation of DNA damage in both stem cells and cells that comprise the stem cell microenvironment is responsible, at least in part, for stem cell dysfunction with aging.

Hematopoietic stem cells (HSCs) regenerate the blood system throughout life and maintain homeostasis.[7] DNA strand breaks accumulate in long term HSCs during aging.[8][9] This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence.[9] DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by non-homologous end joining (NHEJ). Lig4 deficiency in the mouse causes a progressive loss of HSCs during aging.[10] These findings suggest that NHEJ is a key determinant of the ability of HSCs to maintain themselves over time.[10]

A key aspect of hair loss with age is the aging of the hair follicle.[11] Ordinarily, hair follicle renewal is maintained by the stem cells associated with each follicle. Aging of the hair follicle appears to be primed by a sustained cellular response to the DNA damage that accumulates in renewing stem cells during aging.[12] This damage response involves the proteolysis of type XVII collagen by neutrophil elastase in response to the DNA damage in the hair follicle stem cells. Proteolysis of collagen leads to elimination of the damaged cells and then to terminal hair follicle miniaturization.

Diseases such as Alzheimer's disease, end-stage renal failure and heart disease are caused by different mechanisms that are not related to stem cells. Also, some diseases related to hematopoietic system, such as aplastic anemia and complete bone marrow failure, are not especially age-dependent. Aplastic Anemia is often an adverse effect of certain medications [13] but as such it cannot really be considered as evidence against the stem cell theory of aging. The cellularity of the bone marrow does decrease with age and can be usually calculated by the formula 100-age, and this seems consistent with a stem cell theory of aging.[14] A dog study published by Zaucha J.M, Yu C. and Mathioudakis G., et al. also shows evidence against the stem cell theory. Experimental comparison of the engraftment properties of young and old marrow in a mammal model, the dog, failed to show any decrement in stem cell function with age.[15]

The aging process can be explained with different theories. These are evolutionary theories, molecular theories, system theories and cellular theories. The evolutionary theory of ageing was first proposed in the late 1940s and can be explained briefly by the accumulation of mutations (evolution of ageing), disposable soma and antagonistic pleiotropy hypothesis. The molecular theory of ageing includes phenomena such as gene regulation (gene expression), codon restriction, error catastrophe, somatic mutation (accumulation of genetic material damage) and dysdifferentiation (DNA damage theory of aging). The system theories include the immunologic approach to ageing, rate-of-living and the alterations in neuroendocrinal control mechanisms. (See homeostasis). Cellular theory of ageing can be categorized as telomere theory, free radical theory (free-radical theory of aging) and apoptosis. The stem cell theory of aging is also a sub-category of cellular theories.

• Sharpless NE, DePinho RA (2004). "Telomeres, stem cells, senescence, and cancer". J. Clin. Invest. 113 (2): 160–168. doi:10.1172/JCI200420761. PMC 311439. PMID 14722605.
• Chang S, Khoo CM, Naylor ML, Maser RS, DePinho RA (2003). "Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression". Genes Dev. 17 (1): 88–100. doi:10.1101/gad.1029903. PMC 195968. PMID 12514102.
• Metcalfe JA, et al. (1996). "Accelerated telomere shortening in ataxia telangiectasia". Nat. Genet. 13 (3): 350–353. doi:10.1038/ng0796-350. PMID 8673136.
• Hastie ND, et al. (1990). "Telomere reduction in human colorectal carcinoma and with ageing". Nature. 346 (6287): 866–868. Bibcode:1990Natur.346..866H. doi:10.1038/346866a0. PMID 2392154.
• Allsopp RC, et al. (1992). "Telomere length predicts replicative capacity of human fibroblasts". Proc. Natl. Acad. Sci. U.S.A. 89 (21): 10114–10118. Bibcode:1992PNAS...8910114A. doi:10.1073/pnas.89.21.10114. PMC 50288. PMID 1438199.
• Frenck RW Jr, Blackburn EH, Shannon KM (1998). "The rate of telomere sequence loss in human leukocytes varies with age". Proc. Natl. Acad. Sci. U.S.A. 95 (10): 5607–5610. Bibcode:1998PNAS...95.5607F. doi:10.1073/pnas.95.10.5607. PMC 20425. PMID 9576930.
• Liu Y, Sanoff H, Cho H, Burd C, Torrice C, Ibrahim J, Thomas N, Sharpless N (2009). "Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging". Aging Cell. 8: 439–448. doi:10.1111/j.1474-9726.2009.00489.x. PMC 2752333. PMID 19485966.
• Warner HR (Nov 2007). "Kent award lecture: is cell death and replacement a factor in aging?". J Gerontol A Biol Sci Med Sci. 62 (11): 1228–32. doi:10.1093/gerona/62.11.1228. PMID 18000142.
• Bell DR, Van Zant G (2004). "Stem cells, ageing, and cancer: Inevitabilities and outcomes". Oncogene. 23 (43): 7290–7296. doi:10.1038/sj.onc.1207949. PMID 15378089.
• Weinert BT, Timiras PS (2003). "Invited Review: Theories of Aging". J Appl Physiol. 95 (4): 1706–1716. doi:10.1152/japplphysiol.00288.2003. PMID 12970376.
• Kirkwood TB (Feb 2005). "Understanding the Odd Science of Aging". Cell. 120 (4): 437–447. doi:10.1016/j.cell.2005.01.027. PMID 15734677.
• Jones DL, et al. (May 2011). "Emerging Models and Paradigms for stem cell ageing". Nat Cell Biol. 13 (5): 506–512. doi:10.1038/ncb0511-506. PMC 3257978. PMID 21540846.
• Smith JA, Daniel R (Jun 2012). "Stem Cells and Aging: A Chicken-Or-Egg Issue?". Aging and Disease. 3 (3): 260–268. PMC 3375082. PMID 22724084.
• Liang Y, Zant GV (2008). "Aging stem cells, latexin, and longevity". Experimental Cell Research. 314 (9): 1962–1972. doi:10.1016/j.yexcr.2008.01.032. PMC 2471873. PMID 18374916.
• Zant GV, Liang Y (2003). "The role of stem cells in aging". Experimental Hematology. 31 (8): 659–672. doi:10.1016/S0301-472X(03)00088-2. PMID 12901970.
• Rao MS, Mattson MP (2001). "Stem cells and aging: expanding the possibilities". Mechanisms of Ageing and Development. 122 (7): 713–734. doi:10.1016/s0047-6374(01)00224-x. PMID 11322994.
• Marley SB, Lewis JL, Davidson RJ, et al. (1999). "Evidence for a continuous decline in hematopietic cell function from birth: application to evaluating bone marrow failure in children". Br J Haematol. 106 (1): 162–166. doi:10.1046/j.1365-2141.1999.01477.x. PMID 10444180.

• An outline about aging theories from University of California, Berkeley
• A brief summary of rate-of-living theory from Cornell University