Fight Aging!

The biotechnology that spirals out from the study of calorie restriction and metabolic determinants of longevity is growing in breadth. Sirtuins and companies like Sirtris are (unfairly or not) yesterday's news already - the big deals are done, and now it's down to the very unromantic grind of pushing an incrementally better drug for an age-related disease through the horror show that is FDA approval. Beyond sirtuins lie investigations of autophagy, of fat metabolism, and of course the heat shock proteins (HSPs), amongst other items. Looking ahead, I think there's a fair case to be made for the next Sirtris to be a company in the business of manipulating heat shock proteins, aiming to extend life and add healthy years - at least at the outset.

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. This tag, called ubiquitin, directs the misfolded protein to a cellular apparatus known as the proteasome, whose function is to degrade the toxic protein into its constituent amino acids for recycling.

Damaged proteins and damaged cellular components are themselves a source of further damage, as they cause the cell's machinery to run awry - and aging itself is nothing more than the accumulation of damage and its side-effects. The goal of a number of groups working on heat shock proteins is, ultimately, to slow down the progression of aging by boosting the beneficial activities of these and other chaperones. The FDA, however, does not consider aging a medical condition, and thus will not approve any therapy aimed at slowing the pace of aging - so the profit-making research and development of potential first generation longevity therapies is all sidelined into providing some small benefit in the late stages of age-related diseases.

The present hope for advocates such as myself is that the fundamental research performed prior to this inevitable sidelining is still useful, still available to the broader scientific community, and still advances the state of the art - and that it will be picked up for later development in regions where appointed and largely unaccountable officials don't threaten to throw people into jail for developing and marketing longevity medicine. But I digress.

One of the companies presently working on manipulation of molecular chaperones is CytRx. Via one of their recent releases, I was directed to this presently open access paper:

The transcription factor HSF1 initiates the prolific induction of HSP when cells are exposed to protein damage. HSPs are molecular chaperones that protect the proteome by folding denatured polypeptides and promoting the degradation of severely damaged proteins. Activation of HSF1 is coupled functionally to fundamental pathways of longevity and orchestrates the evasion of aging through HSP induction and antagonism of protein aggregation. In addition to mediating protein quality control, some HSPs such as Hsp27 and Hsp70 directly protect cells against damage-induced entry into death pathways.

However, the heat shock response declines in potency over the lifetime, and enfeeblement of the response contributes to aging by permitting the emergence of protein aggregation diseases, reduction in cellular vigor and decreased longevity. ... Molecular chaperones play an important role in the deterrence of protein damage during aging and their expression is required for longevity. Chemical stimulation of HSP synthesis might therefore be a significant strategy in future design of antiaging pharmaceuticals.

On this subject, you might recall the work of Cuervo on restoring function to aging tissue by restoring the process of chaperone-mediated autophagy to youthful levels.

Dr. Cuervo found that the chaperone surveillance system, in particular, becomes less efficient as cells become older, resulting in a buildup of undigested proteins within the cells. She also detected the primary cause for this age-related decline: a fall-off in the number of lysosomal receptors capable of binding chaperones and their damaged proteins. Could replenishing lost receptors in older animals maintain the efficiency of this protein-removal system throughout an animal's lifespan and, perhaps, maintain the function of the animal's cells and organs as well?

Which it did, to deserved acclaim. That researcher makes the point again in a recent review paper:

This review discusses chaperone-mediated autophagy (CMA), a type of autophagy set apart from other autophagic pathways owing to its selectivity and distinctive mechanism by which substrates reach the lysosomal lumen. CMA participates in quality control and provides energy to cells under persistently poor nutritional conditions. Alterations in CMA have recently been shown to underlie some severe human disorders for which the decline with age in the activity of this pathway might become a major aggravating factor. Prevention of the age-dependent decline in CMA has major beneficial effects on cellular and organ homeostasis and function, revealing that CMA is an essential component of the anti-aging fight.

This sort of thing seems to be where the field of metabolic manipulation is headed next.

Calderwood, S., Murshid, A., & Prince, T. (2009). The Shock of Aging: Molecular Chaperones and the Heat Shock Response in Longevity and Aging – A Mini-Review Gerontology, 55 (5), 550-558 DOI: 10.1159/000225957