Fight Aging!

The evidence for metformin to do anything meaningful to longevity in animal studies is fairly ragged - similar studies show a range of results, none of them spectacular, and many of them too small to be significant. It is a marginal candidate for a drug to slow aging when compared to, say, rapamycin, which has much more robust results in animal studies. Further, the whole business of trying to slightly slow aging by tinkering with the ongoing operation of metabolism, slowing the pace at which the cell and tissue damage that causes aging accumulates, is itself an expensive exercise in achieving marginal results. I have to imagine that the reason the TAME human study of metformin and measures of aging exists is not to achieve useful results, but as a form of pressure on the FDA to start accepting treatments for aging. Since metformin has been approved and widely used for decades, the options for rejecting the trial were limited, and once any such trial has been accepted, the next will be easier to push through the established resistance to considering aging as a condition to be treated.

There are a limited number of core mechanisms involved in the link between metabolism and natural variations in longevity, but since all aspects of cellular biochemistry are connected to one another there are any number of ways to influence those core mechanisms. The enormous complexity of molecular biology makes it very hard to map these connections. That work is ongoing now and will be for a long time yet. Thus as a general rule we shouldn't be surprised to learn of newly discovered links between any two of the many approaches demonstrated to modestly slow aging in laboratory species. Here researchers connect metformin with mTOR, the target of rapamycin. mTOR forms two complexes, mTORC1 and mTORC2, and most of the interesting and beneficial effects observed involve suppression of mTORC1. That mTORC2 is suppressed as well is the cause of a number of the harmful side-effects. So there has been some interest in finding ways to target only mTORC1. In that context, it is interesting to see evidence for metformin to be acting in that way, but it doesn't change the basic point that this is all a very marginal exercise with little expected utility for human longevity at the end of the day.

Metformin has been used to treat type 2 diabetes (T2D) for nearly 60 years. It also has potential benefit in cancer prevention and treatment. The class of drugs to which metformin belongs, the biguanides, inhibit cellular growth in a variety of cancer cell lines, particularly in melanoma and pancreatic cancer cells. While it is widely accepted that the mitochondrion is a primary target of metformin, exactly how mitochondrial inhibition by metformin is transduced to the drug's other health-promoting effects, including its anticancer properties, remains unclear. Mitochondrial inhibition by metformin causes energetic stress, which results in activation of the energy sensor adenosine monophosphate-activated protein kinase (AMPK). However, multiple lines of evidence indicate that AMPK is dispensable for metformin's beneficial effects, invoking other major metformin effectors downstream of mitochondria.

The protein kinase mechanistic target of rapamycin complex 1 (mTORC1), which also serves as an energy and nutrient sensor, plays a central role in regulating cell growth, proliferation and survival. Inhibition of mTORC1 activity has been reported in cells in culture treated with metformin, suggesting that reduced TOR activity may be important for the metabolic effects of biguanides. In support of this idea, both metformin and canonical mTOR inhibitors have highly similar effects on the transcriptome, selectively decreasing mRNA levels of cell-cycle and growth regulators. Metformin may inhibit mTORC1 via modulation of Rag GTPases, but the mechanism by which this occurs is uncharacterized. It has been suggested that the pathway that leads to metformin-mediated inhibition of mTORC1 could represent a distinct mechanism of mTORC1 regulation, since no signaling pathway has been identified that connects the mitochondrion to mTORC1 without involvement of AMPK. Whether a mitochondrial-mTORC1 signaling relay plays a role in the action of metformin is still unknown.

As in mammals, metformin promotes health and extends lifespan in C. elegans, raising the possibility of conservation of genetic pathways responsible for metformin's beneficial effects. Using unbiased, iterative genetic screens in C. elegans, we identified a single, central genetic pathway by which metformin regulates growth. We report two elements absolutely required for the anti-growth properties of metformin: the nuclear pore complex (NPC), and acyl-CoA dehydrogenase family member 10 (ACAD10). These two metformin response elements were used to illuminate the major, biological pathway through which metformin induces its favorable effects. Remarkably, this ancient pathway unifies mitochondria, the NPC, mTORC1, and ACAD10 into a single signaling relay that mediates metformin's anti-aging effects in C. elegans and inhibits growth in C. elegans and human cancer cells alike.

Link: http://www.cell.com/cell/fulltext/S0092-8674(16)31667-1