Increasing NAD to Reduce HIF-1 Reverses Age-Related Inflammation and Insulin Resistance in Muscle Tissue

There has been a fair amount of research into the effects of manipulating hypoxia-inducible factor 1 (HIF-1) in lower animals, mostly nematode worms I believe. Interestingly this is one of the few manipulations in which either reducing or increasing levels of the protein in question can increase longevity. This is a sign that there is probably significant complexity involved in this outcome, such as in relationships with other mechanisms or that the effects of changes are tied to specific tissues in the body or locations within cells.

Researchers are today announcing - and, I think, overhyping - new research into a way to manipulate HIF-1 that is apparently an offshoot of past and ongoing research into sirtuins and aging. When considering the source of the work, the overhyping is perhaps less of a surprise than it might otherwise be: this is a group with a very large sunk cost behind them and little to show for it. Deep pockets nonetheless still back continued efforts, and they have a lot of experience with the press. This is a formula that leads to breathless press materials touting rejuvenation. The people who are really, actually working on rejuvenation are more restrained these days.

So let's start by noting that I disagree with the title of the article quoted below. I think that (a) these researchers have found an interesting set of interactions to help explain why manipulation of HIF-1 can affect longevity, and (b) the changing levels of that and various related proteins with advancing age are responses to accumulated cellular damage. Perhaps the most relevant damage is mitochondrial, given that cycling of NAD is involved in the chain of unpleasant results that unfold when mitochondrial DNA becomes damaged, or perhaps it is something else.

So to my eyes what they focus on isn't a cause, it's a consequence. The fastest way to see what causes what at this point is to work on repairing the known forms of damage rather than tracing back all of the myriad complexity of relationships and feedback loops in the cell - a task that would take substantially longer than just building means of biological repair for our cells and other small-scale structures.

A New - and Reversible - Cause of Aging

Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which [the] SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell's nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell's nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1's role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.

For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell's ability to make energy, and signs of aging and disease become apparent.

While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough - prior to excessive mutation accumulation - within days, some aspects of the aging process could be reversed.

Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.