Fight Aging!

The Lifespan.io crew have launched their latest longevity science crowdfunding project in partnership with the Sinclair lab at Harvard: the goal is to raise funds for a novel calorie restriction mimetic mouse life span study based on research published last year. You might recall that David Sinclair was the researcher behind Sirtris, one of the more hyped initiatives in sirtuin research, though far from the only one. Over the past twenty years a lot of work has gone into trying to understand the activities of proteins and pathways thought to be important in the extended longevity produced by calorie restriction in short-lived species, sirtuins among their number, and there was considerable enthusiasm for drug development along these lines a decade ago. A few companies were founded, such as Sirtris, but while some people made a bunch of money, nothing came out of this save for a greater appreciation of the complexities of cellular metabolism and a mountain of new data.

Research on sirtuins didn't halt following the realization that this wasn't a fast path to modestly slowing the aging process. It continues, along with a great many other, similar investigations into the detailed operation of mammalian biochemistry, and how it changes in response to circumstances. In fact much of aging research and longevity science even now is arguably just a thin excuse to bring funds into the grand endeavor of mapping cellular metabolism, in much the same way that Alzheimer's research is used as the rallying banner for fundamental work on understanding the biochemistry of the brain. Decades of work remain to be accomplished in the project of mapping metabolism in the context of aging, even given the advanced tools of modern biotechnology. Actions speak louder than words, and most scientists in the field are doing a lot more mapping than work on potential treatments for aging.

So what are the researchers at the Sinclair lab up to these days? You might recall that they are investigating possible drug candidates to alter the behavior of mitochondria for the better in aged tissues, which is another line of research fairly closely connected to calorie restriction. This particular approach involves manipulating nicotinamide adenine dinucleotide (NAD) levels using compounds such as nicotinamide mononucleotide (NMN) or precursors. NAD levels decline with aging, decline more slowly in calorie restricted individuals, and restoring NAD levels artificially has been shown to produce some benefits in old mice. However there is yet a lot of uncertainty in this; it is a good thing at this point to remember the data on and view of sirtuins and their relevance to aging, and how that changed over time. For my money the research on this to date at the Sinclair lab is much more interesting for the connections it exposes between mitochondria, nutrient sensing, and regulation of cellular maintenance, some of the foundation stones for the operation of hormesis, than as the basis for therapies.

Can NMN Reverse the Effects of Aging in Mice?

One of the best studied anti-aging treatments is a diet reduced in calories, yet high enough in nutrients to avoid malnutrition. Known as calorie restriction (CR), this dietary regimen provides irrefutable evidence of the importance of metabolism in the aging process. While CR has been studied extensively and even tested in human trials, long term adherence to a CR dietary regimen is extremely difficult for most individuals to maintain. One method to achieve the benefits of CR for everyone would be to administer compounds which act as a "CR mimetic." Such compounds are capable of stimulating the cellular signaling cascades that are normally induced during CR. Over the past 20 years, we have made great strides in understanding the key cellular components involved in mediating many of the metabolic changes that contribute to the aging process.

A major metabolic signaling molecule that we and others have shown to exhibit significant declines with increasing age is NAD+. Importantly, CR reverses the age-related decline of bioavailable NAD+. This key metabolite plays a crucial role in regulating the activity of many important signaling molecules involved in age-related diseases. However, feeding or administering NAD+ directly to organisms is not a practical option. The NAD+ molecule cannot readily cross cell membranes and therefore would be unavailable to positively affect metabolism. Instead, precursor molecules to NAD+ must be used to increase bioavailable levels of NAD+.

One such metabolic precursor of NAD+, niacin, is currently used as a medical therapeutic in humans to regulate blood lipid profiles and ward off cardiovascular disease. Niacin, however, has unwanted side-effects and is separated by too many metabolic steps upstream of the final production of cellular NAD+ to substantially impact the magnitude of NAD+ bioavailability. Recently, we have shown that by administering the NAD+ precursor NMN (Nicotinamide Mononucleotide) in normal drinking water, bioavailable NAD+ levels were restored to those normally associated with younger healthy animals. By administering NMN to mice for just one week, our lab demonstrated a robust correction in age-associated metabolic dysfunction and restored muscle function in old mice to levels seen in younger control mice.

In our project, we will test the hypothesis that by restoring bioavailable NAD+, we can reverse the aging process. Starting with mice that are one year old (roughly equivalent to a 30 year old human), longer-term NMN treatments will be applied in order to restore levels of cellular NAD+ to those found in youthful mice. Along with a large cohort of normal mice, a novel genetically engineered mouse, termed the ICE mouse (Induced Change in Epigenetics) will be used during the trial. These ICE mice manifest an accelerated aging phenotype and as a result are short lived. By using ICE mice in our trial, in addition to normal control mice, we will be able to more rapidly test the effectiveness of potential anti-aging treatments, such as NMN, thus obtaining faster experimental results.

Your donations will not only allow us to purchase the materials necessary to perform this experiment, but also open the doors to working together with you in the future eventually leading to human clinical trials aimed at showing, for the first time, that we can actually slow down human aging.

As I'm sure you're all aware by now, I'm really not in favor of traditional drug development with the goal of modestly slowing the aging process. The prime example of this is any attempt to recapture some fraction of the effects of calorie restriction by tinkering with the operation of metabolism. One of the good things to come out of years of sirtuin research is that it now serves as a calibration point to demonstrate (a) just how expensive it is to try to manipulate the operation of metabolism with drugs, even when seeking to recreate a well-studied and easily reproduced natural metabolic state like the calorie restriction response, and (b) just how unlikely it is for this sort of approach to produce useful therapies, even given large investments of time and money. So I'd say that helping to fund this proposed life span study in mice using nicotinamide mononucleotide as a calorie restriction mimetic should be approached with the view that you are assisting fundamental research with the aim of understanding more of the relationships between mitochondria, calorie restriction, and aging, not that you are assisting an approach likely to lead to useful therapies in humans. Clearly life span studies like this are useful fundamental life science research, of the sort undertaken by the Interventions Testing Program and the NIA, who never have enough funding to do as much as they'd like to do, but they are not in the same class of expected value as SENS rejuvenation research projects.