A Look at the Camp of Slowing Aging via Metabolic Alteration

As I'm sure the regular readers know by now, researchers interested in extending human life span form a minority community within the broader medical research establishment. In that small community, most scientists see the best path ahead as a slow, incremental, and challenging process of finding ways to safely alter metabolism in order to modestly slow down the aging process. They don't expect significant progress in anything other than fundamental research and discovery of mechanisms any time soon. The alternate approach of reversing the known forms of damage that cause degenerative aging, so as to aim for rejuvenation, remains as yet a minority position - sadly, because it is the only plausible chance at radical life extension of decades and more within our lifetimes.

For today, let us look at the metabolic alteration camp, however. What are their aims in greater detail? To begin with, a lot of research has spiraled out from investigations of calorie restriction - which is, after all, an evolved way to shift the operation of metabolism such that aging is slowed and life span extended. Billions of dollars have been funneled into trying to understand how this works, in search of ways to replicate some of the same effects.

Understanding in this context means building a map of the various signals, proteins, epigenetic alterations, and so forth: knowing how they flow from one to another and act as a network in unison. The work accomplished to date is just a beginning, even billions of dollars and more than a decade down the line, however. Metabolism is very, very complex, and thus at this point there is little of practical worth to show for all this time and money. Sufficient understanding to produce even moderately effective and safe calorie restriction mimetic drugs still lies in the future.

Other lines of research are underway: metabolic alteration is not just a field focused on calorie restriction these days. Below you will find a couple of open access publications that give some insight into how the researchers focused on metabolic manipulation to slow aging presently see the state of play. It is very similar to that landscape of drug discovery and development for complex and only partially understood diseases like Alzheimer's: a matter of uncovering new information that proceeds hand in hand with the evaluation of classes of protein that might be manipulated with designer drugs to achieve some beneficial effect with hopefully minimal side-effects. Indeed, one of the reasons that this hard, inefficient approach to extending healthy life does presently dominate over other, superior approaches - such as the goal of periodic repair for cellular and other biological damage - is that it can be treated as an extension of existing drug discovery programs. The power of inertia in the culture of research shouldn't be underestimated: we humans don't like change, even when beneficial.

Epigenetic drugs: a novel anti-aging strategy?

In this Opinion, we present arguments that the development of specific drugs which target epigenetic pathways could be a highly promising anti-aging strategy. Epigenetic factors including DNA methylation, histone modifications, and alteration in microRNA expression play key roles in controlling changes in gene expression and genomic instability throughout the human lifespan. Epigenetic modifications are finely balanced and highly reversible in normal tissues.

Histone deacetylases (HDACs) are global transcriptional regulators; [the] therapeutic effects of HDAC inhibitors are based on their ability to affect the transcription of various genes ... Overall, as a major mechanism of transcriptional regulation, protein acetylation is a key controller of many physiological processes essential for the maintenance of homeostasis and a healthy lifespan. Consequently, it is believed that the development of specific drugs which target HDAC activity could be a highly promising anti-aging strategy.

Notwithstanding all doubts, in recent years, experimental research has emerged on the life-extending potential of synthetic HDAC inhibitors. A substantial increase in both mean and maximum survival by up to 30-50% without diminution of locomotor activity, resistance to stress, or reproductive ability was observed by feeding Drosophila melanogaster the HDAC inhibitor, PBA (4-phenylbutyrate), throughout adulthood.

In conclusion, understanding the molecular mechanisms underlying the protective role of HDAC inhibitors and other modulators of epigenetic processes could bring us closer to the development of novel drug targets for age-associated chronic diseases. In our opinion, this approach may also provide a new way for the development of efficient anti-aging treatments.

The spatiotemporal dynamics of longevity-defining cellular processes and its modulation by genetic, dietary, and pharmacological anti-aging interventions

Aging of multicellular and unicellular eukaryotic organisms is a highly complex biological phenomenon that affects a plethora of processes within cells. ... The focus of this Frontiers Special Topic Issue is on an important conceptual advance in our understanding of how cells integrate and control these numerous processes and how genetic, dietary, and pharmacological anti-aging interventions extend longevity by altering their functional states and spatiotemporal dynamics.

Collectively, the articles in this Issue highlight the various strategies used by evolutionarily diverse organisms for coordinating these longevity-defining cellular processes in space and time, critically evaluates the molecular and cellular mechanisms underlying such coordination, and outlines the most important unanswered questions and directions for future research in this vibrant and rapidly evolving field.

There is plenty of reading material to found by diving in to follow the links embedded in the second item above.


any good mice studies (mammals) with HDAC inhibitors and lifespan?

Posted by: Alan Donahue at November 10th, 2012 10:52 AM
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