There are a score or more ways to reliably slow aging in mice, methods that include a few classes of drug, various single gene alterations, and calorie restriction. The most exceptional of these methods extends life by 60% or so, but most are in the much more modest 10-20% range at best. It is suspected that many of these approaches operate on a smaller overlapping set of underlying processes, but at different entry points: metabolism is a very, very complex system of interactions and feedback loops, and it is near impossible to make any change in isolation. Any given portion of our biochemistry distinct enough to be given a name and studied might consist of dozens of proteins at its core, and interact with hundreds more in ways that are important when considering the pace of aging.
To pick one example, increased levels of the cellular housekeeping processes called autophagy show up in many ways of slowing aging in lower animals. Some of the methods of slowing aging may only work at all because they happen to influence cells into taking better care of themselves, but that influence doesn't have to be in any way direct. Some alterations to mitochondria known to extend life in nematode worms slightly raise the generated levels of damaging reactive oxygen species emitted by mitochondrial processes, and that in turn causes cells to react with greater housekeeping vigor for a net gain. Much the same net gain might also be achieved by more direct manipulations that increase levels of autophagy - but from a distance these two approaches look very different, and target quite different proteins.
Thus the challenge facing researchers interested in slowing aging is that they are in no way even close to fully understanding any of the easily replicated and studied methods of slowing aging in various laboratory animals. Decades of work lie ahead to make a serious dent in the great unknowns of how metabolism interacts with aging in detail, even with the expected increases in computing power and new tools in biotechnology. This is why researchers are not generally all that optimistic about progress in the near term via calorie restriction mimetics and other ways of altering metabolism to slow aging. It is why I favor approaches such as SENS that largely bypass expensive attempts to change metabolism in favor of repairing clearly identified age-related changes in tissues, with the expectation that lacking this damage the operation of metabolism will revert back to the known good state that exists in youth, when comparatively little of that damage is present.
Most ongoing work in the aging research community focuses on finding out more about metabolism and aging, however, with some interest in ways to slow aging. It is quite often fascinating stuff, such as the open access paper below, but bear in mind that this really isn't a path to much more than knowledge. From the practical standpoint of whether we are on the road to greatly extend healthy life and reverse aging in the near future, this is not the way forward.
ATF4 is a transcriptional factor which senses deficits in protein translation, typically related to endoplasmic reticulum stress or amino acid limitation, and in turn activates a group of target genes. The availability of multiple methods to extend mouse maximal lifespan - genetic, dietary, development, or drug-induced - provides an opportunity to test the hypothesis that augmented ATF4 action, necessary for multiple modes of lifespan extension in yeast, is also characteristic of slow aging in mice.
Data in this paper show that ATF4 levels, levels of proteins controlled by ATF4, and levels of three mRNAs regulated directly by ATF4 are elevated in liver of mice exposed to each of five interventions shown elsewhere to increase maximal longevity: the drugs acarbose and rapamycin, diets low in calories or methionine, or transient milk deprivation limited to the suckling period.
Our previous work has shown similar increases in ATF4 protein and downstream indicators of ATF4 function in liver of Snell dwarf mice and PAPP-A knock-out mice, mutations that increase maximal lifespan and health in old age by alteration of endocrine pathways connected to GH and/or IGF-1. The previous study also documented augmented ATF4 responses in fibroblast cell lines derived from skin of adult Snell and PAPP-A KO mice, suggesting that the relevant changes affect more than a single cell type and that the changes include epigenetic modifications preserved during multiple mitotic cycles in tissue culture medium. All of these data are consistent with the idea that elevation of ATF4 function may contribute to the slow aging and extended lifespan in each of these diverse varieties of mice.
You might recall that ATF4 shows up in studies of methionione restriction. It is thought that a fair fraction of the benefits of calorie restriction involve changes in the operation of metabolism triggered by mechanisms that react to low methionine levels. You might look at these past items from the Fight Aging! archives for more context:
The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed.
Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight.