Linking Autophagy to Insulin Signaling in Longevity

The protein signaling mechanisms surrounding insulin and insulin-like growth factor (IGF-1) are one of the better studied portions of the overlap between metabolic biochemistry and natural variations in longevity. They influence all of the core aspects of our biology: growth, regeneration, and other vital cell activities. Thus despite the years of work researchers still lack a truly clear picture of how it all fits together: this is a ferociously complex area of study, in which every molecular mechanism influences many other molecular mechanisms. Isolating any one portion of the interlinked systems making up the biology of life is next to impossible.

Another comparatively well-studied and related area is autophagy, the collection of quality control processes by which cells clear out damaged components and unwanted waste compounds. More autophagy is consistently linked to enhanced longevity in laboratory animals, and shows up as a candidate mechanism for the extended life generated by a range of genetic alterations and environmental changes, such as the practice of calorie restriction. This makes sense: aging is most likely nothing more than an accumulation of damage, and more autophagy means less of that damage accumulating per unit time. Many researchers think that when it comes to slowing aging all roads lead to improved autophagy. Surprisingly, there hasn't been as much of a drive to produce autophagy-enhancing drugs as I would have expected by this time, despite some quite compelling demonstrations of the restored organ function that could be produced in old patients.

Here we have research that bridges the two regions of study I've sketched above: tracing the alterations to metabolism that link insulin and insulin-like signaling with autophagy.

Protein interplay in muscle tied to life span

Fruit flies are notoriously short-lived but scientists interested in the biology of aging in all animals have begun to understand why some fruit flies live longer than others. They have documented a direct association between insulin and life span, for example, and have observed a tradeoff between prolific reproduction and longevity. A new study, which may have broad implications across species, ties those findings more closely together by tracing an insulin signaling cascade through to protein quality control in muscle tissue and shortened life span.

The central feature of the study [is] the newly discovered role of the fruit fly equivalent of the mammalian protein complex activin. They found that it blocks the natural mechanism in muscle cells for cleaning out misfolded proteins, leading to a decline in muscle performance. In what [scientists] think is no coincidence, blocking the activity of that activin equivalent, called dawdle, can lengthen a fly's life span by as much as 20 percent, about 10 days.

Activin Signaling Targeted by Insulin/dFOXO Regulates Aging and Muscle Proteostasis in Drosophila

It is widely known that reduced insulin/IGF signaling slows aging in many contexts. This process requires the forkhead transcription factor (FOXO). FOXO modulates the expression of many genes, and the list of those associated with slow aging is impressive. But there are few data indicating the mechanisms or genes through which FOXO actually slows aging. Here, we identify a novel FOXO target, dawdle, the Activin-like ligand in fruit flies.

Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan.

These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling.

Not surprisingly, the details uncovered by these researchers have the look of a two-way feedback loop. Little in biology is a one-way street, which is one of the many reasons it is very hard to even understand the metabolism of longevity, let alone safely alter it. The existence of this complexity is why I favor strategies for enhancing longevity that do not rely upon altering an aged metabolism, but instead aim to restore it to a youthful state by repairing damage. This is an important distinction to make, and it will become ever more important in the years ahead.

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