Most of the interventions and genetic alterations shown to slow aging in laboratory species are operating through some combination of the same set of underlying stress response mechanisms, the quality control and repair systems that step up their operation in response to nutrient deprivation and other stresses. Therefore is isn't surprising that the research community continues to discover shared mechanisms and regulators that, if disabled, will prevent numerous interventions from working to extend life in animal studies.
The research here, in which the gene ATGL-1 is identified as vital to such a shared mechanism, is interesting from a pure science perspective. It is another step forward in understanding how stress responses systems interact with the pace of aging. It isn't, however, going to be all that useful in the process of building therapies to extend human life. In our species, unlike short-lived species such as flies, worms, and mice, greater activity of stress response mechanisms does not greatly alter length of life. That said, the data obtained from the practice of calorie restriction shows that it has a large enough positive impact on health to be well worth considering as a lifestyle choice - larger than near any medical technology is so far proven to provide to basically healthy individuals.
Still, even given sizable health benefits, relative to the present bounds of the possible, producing therapies that mimic the response to calorie restriction or other stresses is not the path forward to meaningful rejuvenation of the old. These approaches do not do enough to address the underlying damage that causes aging. They don't reverse it to a great enough degree, and they don't slow it down enough to escape the current limits on the human life span. We need means of deliberate repair of the underlying damage that causes aging in order to produce rejuvenation, not means of adjusting metabolism into a somewhat more resilient state, that little more able to resist the damage.
In metazoans, the insulin/IGF1 signaling pathway (IIS) coordinates nutrient and energy availability with growth, metabolism, and longevity. Two major "signaling nodes", FoxO- and TORC1-centered, are responsible for the effect of nutrients and IIS on the lifespan. Transcription factor FoxO1 that adapts mammalian organisms to starvation is negatively regulated by IIS via Akt-mediated phosphorylation and nuclear exclusion. At the same time, TORC1 (Target Of Rapamycin Complex 1) is activated by Akt and nutrients and promotes anabolic processes while inhibiting catabolism.
The downstream targets of FoxO and TORC1 that transmit longevity signals remain largely unknown. Given that both FoxO and TORC1 are ubiquitously expressed and regulate a plethora of important biological responses, identification of the specific pathways that control longevity is challenging. In fact, we do not even know whether FoxO and mTORC1 are involved in the same pathway or mediate different pathways of the longevity control.
We have recently found that FoxO1 and mTORC1 control the rates of lipolysis in mammalian cells by regulating expression of adipose triglyceride lipase (ATGL). Although complete hydrolysis of triglycerides to glycerol and fatty acids is performed jointly by tri-, di-, and monoacylglyceride lipases, ATGL represents the rate-limiting lipolytic enzyme. In other words, in every mammalian experimental system tested thus far, elevated ATGL expression increases, while attenuated ATGL expression decreases, lipolysis.
Since known biochemical pathways that control longevity converge on the regulation of ATGL expression, we have hypothesized that ATGL may represent the long sought after target of the nutrient and insulin/IGF1 signaling pathways that regulate life span. Here, we utilize the nematode C. elegans, a well-characterized and widely used model for longevity studies, and show that expression of the C. elegans ATGL homologue ATGL-1 is controlled by nutrients and the DAF-2/DAF-16 pathway. Moreover, we find that the partial loss-of-function ATGL-1 mutant blocks the life-extending effects of dietary restriction (in the eat-2 loss-of-function model) and DAF-2 deficiency, whereas over-expression of ATGL-1 increases C. elegans lifespan.