Why glycation (AGE-centric) theories of aging are ultimately flawed

[Guest guest]

The contribution of the gradual senescence of progenitor cells and "stem cells" to the "aging process" is something that I think is discounted strongly in the popular imagination, but it is a more significant contributor to physiologic decline than "total lesion burden". The reason this has to be so is simply because the steady-state of lesions is determined at any given time by the number of circulating, "roaming" cells capable of performing the necessary reparative processes.

As "aging" proceeds, the number of cells capable of sustaining repairs gradually declines, and the lesions begin to "overwhelm" the remaining cells. What is important at any given time is not necessarily the lesions themselves, but the number of cells capable of coordinating repairs.

To this end, the recent findings from the Department of Geriatics at Mt. Sinai School of Medicine are very elucidating. They have determined that glomerular aging is reversible, and, very importantly, "....the aging lesions in females were reversible and that progenitors, rather than the local environment, determined the glomerular profile."

So, where are the AGEs now? In the full-text, the following lines are particularly insightful:

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"Thus, the aging lesions are reversible and changes in the composition of the local extracellular matrix do not appear to interfere with the ability of newly arriving normal progenitors or factor(s) to return the architecture to a more normal state. " - PMID: 16049323

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"This finding is the first demonstration of reduced glomerular size and sclerosis mediated by glomerular progenitors derived from an extrarenal source. However, circulating factor(s) derived from the young cells contained in the BMT may also have played a role in reducing the aging lesions, as suggested in a recent study by Conboy and colleagues." - PMID: 16049323

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At the very least, in light of evidence such as this, theories of aging that emphasize the accumulation of lesions in the extracellular matrix need to incorporate a more comprehensive description of the proximate source of elevations of those lesions seen with the passage of time.

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Am J Pathol. 2005 Aug;167(2):355-63.

Related Articles,

Links

Glomerular aging in females is a multi-stage reversible process mediated by phenotypic changes in progenitors.

"Using cross bone marrow transplants (BMT) between young and old females, we found that BMT delivered a phenotype that was donor age-specific....Postmenopausal recipients of BMT from young donors had reduced glomerular hypertrophy and sclerosis, implying that the aging lesions in females were reversible and that progenitors, rather than the local environment, determined the glomerular profile. The altered phenotype included increased extracellular matrix synthesis and decreased matrix metalloproteinase-2 levels as well as cell hypertrophy. The mechanism of the cellular hypertrophy was due to uncoupling of hypertrophy from proliferation, resulting from elevated p27 levels. Thus, glomerular hypertrophy and sclerosis in aging females is a multistage process, is reversible, and may be determined by the phenotype of bone marrow-derived progenitor cells." - PMID: 16049323

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=16049323

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T.

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