Thursday, November 27, 2008

Universal Aging Mechanism?

As an organism changes, its pattern of gene activation/deactivation and repair changes from a vibrant youthful pattern to a less efficient and effective senescent pattern. Harvard scientists are learning more about some of the underlying mechanisms behind this "genetic control shift of aging."
The researchers found in studies of mammalian stem cells that the protein SIRT1 controls the packaging of DNA into chromatin, thereby setting the youthful pattern of gene activity by keeping select genes switched off. In response to DNA damage, those SIRT1 proteins leave their posts to go off and assist in the necessary repairs. That change in SIRT1's job description leads to shifts in gene activity that parallel those seen in the aging mouse brain, they show. They suspect similar changes would also be found in other body tissues as well.

" The critical protein controls both which genes are off and on as well as DNA repair; it's used for both processes, and that's the catch," said David Sinclair of Harvard Medical School. "As cells accumulate DNA damage, the protein can't do both jobs sufficiently." Once SIRT1 loses control, gene activity goes haywire, a state of affairs that leads to symptoms associated with aging.

Sinclair's team also found what they consider to be good evidence that the aging process can be slowed. Mice with an excess of SIRT1 had an improved ability to repair DNA and prevent those unwanted changes in gene expression. The hope is that those improvements could be reproduced with a drug that stimulates SIRT1, they said. _Eurekalert
Permanent gene therapy to boost SIRT1 for both gene repair and maintaining a youthful gene activity pattern seems preferable to a daily pill or injection. In fact, genetic therapy will likely replace most pharmaceuticals as we learn more about the underlying physiology and pathology of our organisms. SIRT1 will be but a small part of the overall story of aging. But for now, it appears to be an important early step in our understanding.


Tuesday, November 11, 2008

MK-677, Oral Ghrelin Mimetic, Stimulates Youthful Pulsatile HGH Secretion in Elderly

Via NextBigFuture, this Annals of Internal Medicine article looks at the effect of an oral ghrelin mimetic on secretion of HGH, and various physical measurements such as muscle mass, visceral fat, etc.
Conclusion: Over 12 months, the ghrelin mimetic MK-677 enhanced pulsatile growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated. Long-term functional and, ultimately, pharmacoeconomic, studies in elderly persons are indicated.

Previous trials in which growth hormone was administered to elderly persons were small, poorly controlled, or too short (8); in addition, growth hormone replacement does not restore pulsatile growth hormone secretion. MK-677, the first orally active ghrelin mimetic (a growth hormone secretagogue and growth hormone secretagogue–receptor agonist), increases pulsatile growth hormone secretion in older adults to levels observed in young adults (9, 10). Our primary objectives were to determine whether 25 mg of oral MK-677 daily would increase growth hormone and insulin-like growth factor I (IGF-I) levels in healthy older adults, prevent the decline in fat-free mass, and decrease abdominal visceral fat, with acceptable tolerability.

...Frailty is one of the scourges of elderly persons, and as researchers are beginning to learn about its causes, they are asking whether growth hormone deficiency is one of them. A systematic review (8) concluded that the risks of exogenous growth hormone outweigh the benefits and that it is not the long-sought solution to frailty. The promise of MK-677 is that it seems to restore endogenous growth hormone levels in a physiologic secretory pattern, unlike the single high-amplitude pulse observed after exogenous growth hormone administration. We believe that our study sets the stage for an adequately powered clinical trial of sufficient duration in a population vulnerable to frailty. _AnnalsIntMed
The effects of the more physiologic pattern of HGH secretion seen in MK-677 recipients vs. standard HGH replacement protocols, suggests that more indirect route of using an oral ghrelin mimetic may provide better long-term results.

The most significant adverse effect was an increase in appetite, which in many elderly might be seen as more of a positive miracle than an adverse effect. I encourage anyone interested to go to the article itself and read it in full. The complexity of homeostasis in the human organism should discourage simplistic and cavalier interventions for purposes of senescence mitigation. The study quoted above is a good example of a thoughtful and fairly comprehensive look at a measured intervention. The findings should be confirmed and integrated into the leading theories of senescence mitigation and reversal.


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