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A Small Selection of Calorie Restriction Mimetic Drug Research

Could a drug introduced in the 2010s be able to induce rejuvenation, the repair of age-related damage? To a very limited degree, yes. We would expect some types of drug, early and poor examples of which are presently undergoing investigation in the laboratory, to be able to stimulate the aged body to repair certain types of cellular damage and aggregate buildup that it would otherwise be unable to deal with - in other words to rejuvenate some aspects of cellular biology to their youthful states of operation. One line of research to this end is based on what has been learned from the study of the biochemistry of calorie restriction and exercise.

A calorie restriction mimetic drug is one that replicates some of the biochemical changes in gene expression and cellular processes caused by calorie restriction - and hopefully thereby also produce noteworthy benefits to health and longevity. No existing medical technology even comes close to what calorie restriction can achieve in humans and other mammals, a fact also true of exercise. The traditional drug industry is sinking vast sums of money into discovering and developing pharmaceutical methods to capture the benefits of calorie restriction and exercise - things that most people won't do for themselves, but will happily pay for in the form of a pill.

Both calorie restriction and exercise share some mechanisms in common, such as improving the operation of heat shock proteins:

Heat shock proteins are molecular chaperones, and their activities in the body are boosted by exercise and calorie restriction, two line items known to extend healthy life in laboratory animals and produce impressive health benefits in humans. Put simply: molecular chaperones detect proteins that are misfolded, and have the ability to refold those proteins into the appropriate, non-toxic shape. Additionally, if the protein is so badly misfolded that it cannot be repaired, the molecular chaperones can also recruit other proteins that have the ability to "tag" the toxic protein for destruction by the cell.

Heat shock proteins are one aspect of the process of autophagy, wherein damaged materials and cellular components are recycled. Calorie restriction may operate largely through boosting autophagy:

the weight of evidence points to more and better autophagy as beneficial overall, most likely because it leads to fewer lingering damaged components inside a cell. Repeated throughout all your cells, this should result in better functioning tissue, fewer errant biological systems, and a longer life - remember that aging itself is nothing more than accumulated damage and the thrashing of systems trying to adapt to that damage.

But it is also hard to discount benefits of calorie restriction that occur due to nothing more than avoiding large amounts of of visceral fat, which greatly reduces chronic inflammation caused by fat deposits.

Not to hammer on the point too much, but excess body fat held over the years causes chronic inflammation, which enrages your immune system, which leads to atherosclerosis, which tends to kill you abruptly and without warning. All very avoidable.

If being charitable, we might think of any drug that boosts autophagy, the operation of heat shock proteins, or one of the other biochemical changes brought on by calorie restriction as a form of calorie restriction mimetic. Researchers are investigating quite a few such drugs these days; I noticed a couple of recent research papers that are illustrative of the sort of work taking place at the moment, and the level of knowledge in the field:

Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1

Metformin, a biguanide drug commonly used to treat type-2 diabetes, has been noted to extend healthspan of nondiabetic mice, but this outcome, and the molecular mechanisms that underlie it, have received relatively little experimental attention. To develop a genetic model for study of biguanide effects on healthspan, we investigated metformin impact on aging Caenorhabditis elegans. We found that metformin increases nematode healthspan, slowing lipofuscin accumulation, extending median lifespan, and prolonging youthful locomotory ability in a dose-dependent manner. Genetic data suggest that metformin acts through a mechanism similar to that operative in eating-impaired dietary restriction (DR) mutants, but independent of the insulin signaling pathway.

17-AAG induces cytoplasmic alpha-synuclein aggregate clearance by induction of autophagy

The accumulation and aggregation of alpha-synuclein in nerve cells and glia are characteristic features of a number of neurodegenerative diseases [such as Parkinson's disease, for example]. alpha-Synuclein is a highly soluble protein which in a nucleation dependent process is capable of self-aggregation. The causes underlying aggregate formation are not yet understood, impairment of the proteolytic degradation systems might be involved.

...

Our data demonstrate that [the drug] 17-AAG attenuated the formation of alpha-synuclein aggregates by stimulating macroautophagy. ... Our data demonstrate for the first time that 17-AAG not only causes the upregulation of heat shock proteins, but also is an effective inducer of the autophagic pathway by which alpha-synuclein can be removed. Hence [this or similar drugs] may provide a means to modulate autophagy in neural cells, thereby ameliorating pathogenic aggregate formation and protecting the cells during disease and aging.

Resveratrol and rapamycin: are they anti-aging drugs?

Studies of the basic biology of aging have advanced to the point where anti-aging interventions, identified from experiments in model organisms, are beginning to be tested in people. Resveratrol and rapamycin, two compounds that target conserved longevity pathways and may mimic some aspects of dietary restriction, represent the first such interventions. Both compounds have been reported to slow aging in yeast and invertebrate species, and rapamycin has also recently been found to increase life span in rodents. In addition, both compounds also show impressive effects in rodent models of age-associated diseases. Clinical trials are underway to assess whether resveratrol is useful as an anti-cancer treatment, and rapamycin is already approved for use in human patients. Compounds such as these, identified from longevity studies in model organisms, hold great promise as therapies to target multiple age-related diseases by modulating the molecular causes of aging.

The resveratrol results in mice are being challenged, however, and were never actually all that impressive in the first place, when considered in comparison to other calorie restriction mimetic candidates. Drugs engineered to boost or repair failing autophagic processes in the old are, to my eyes, the most promising potential outcome of this wide-ranging field of research. Improved autophagy in the old can clear out intracellular aggregates and the buildup of cellular damage, which is exactly a form of rejuvenation - restoring an aspect of the aging cellular environment to youthful levels. Therapies built upon such drugs would be limited to reversing only those forms of age-related damage that autophagy can clean up, but it is nonetheless a form of rejuvenation.

ResearchBlogging.orgOnken, B., & Driscoll, M. (2010). Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1 PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008758

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