A Review of Lifespan, the Book, and Some Confusion About Aging
David Sinclair works on areas of mitochondrial metabolism relevant to aging, sirtuins and NAD, and of late is involved in research into a novel understanding of the relationship between DNA repair and age-related epigenetic change, as well as the use of in vivo reprogramming as a way to reverse age-related epigenetic change. He is first and foremost an excellent self-promoter, however, a job that has come to includes authoring books such as Lifespan.
On balance, self-promotion seems a useful trait for people who work on projects of merit. It is a tough job to raise funds and build the necessary networks of allies to push forward the bounds of any field; every advantage helps. It is not such a good trait when the projects themselves are not useful. Self-promoters have a way of cluttering the road to clear debate and understanding, and Sinclair's work is a mixed bag when it comes to utility as the basis for treatments for aging. That said, I think it unlikely that Altos Labs would exist in its present form, devoting a sizable budget - hundreds of millions initially - towards in vivo reprogramming as an approach to the treatment of aging, absent Sinclair spending the last few years aggressively publicizing his work on reprogramming to everyone who would listen. Fortunately, and unlike everything else Sinclair has worked on and relentlessly publicized to date, in vivo reprogramming is an area of research that might turn out to produce a meaningful degree of rejuvenation in old people.
Unfortunately, this still means that one should take everything Sinclair says outside a peer reviewed scientific paper as propaganda, a matter of talking up his position and enabling the companies he is involved in to raise funds and find exits. Self-promotion is a game in which one can win every battle and still lose the war, as people come to filter everything one says through the lens of self-interest and then disregard it. Perhaps Sinclair believes in the position he puts forward in the book Lifespan, perhaps not, but to present epigenetic change as the whole of aging - which it is most certainly not, and may not even be that close to the root causes - is just too convenient given his portfolio of interests. Maybe he is a true believer in his own work, and that explains it all, but this is also the person who talked up the dead end of sirtuins and resveratrol in exactly the same way fifteen years ago. He overhypes everything that he is earnestly involved in.
I have no horse in this race, beyond a desire to see meaningful progress towards rejuvenation in my lifetime. I've never met the man. It is good that Sinclair is now putting earnest effort into a potential road to therapies - in vivo reprogramming - that might actually have some promise when it comes to human rejuvenation, and has persuaded others with significant resources to do the same. I do wish he would temper the way in which he publicizes and promotes his work, however. It think that it harms long-term prospects for the field more than it helps.
Separately, and to the content of the review here, it is always interesting to see people coming in from the outside the field and describing their confusion on encountering the various competing views of aging and possible paths to the treatment of aging. The confusion is only exacerbated by the degree to which various parties present narrow views of aging, or present their narrow view of aging as the whole of the picture, or leave out inconvenient points that undermine their position. This sort of thing is rife in the scientific literature, and worse in popular science materials.
David Sinclair - Harvard professor, celebrity biologist, and author of Lifespan - thinks solving aging will be easy. "Aging is going to be remarkably easy to tackle. Easier than cancer" are his exact words, which is maybe less encouraging than he thinks. Sinclair thinks aging is epigenetic damage. As time goes on, cells lose or garble the epigenetic markers telling them what cells to be. Kidney cells go from definitely-kidney-cells to mostly kidney cells but also a little lung cell and maybe some heart cell in there too. It's hard to run a kidney off of cells that aren't entirely sure whether they're supposed to be kidney cells or something else, and so your kidneys (and all your other organs) break down as you age. He doesn't come out and say this is literally 100% of aging. But everyone else thinks aging is probably a combination of many complicated processes, and I think Sinclair thinks it's mostly epigenetic damage and then a few other odds and ends that matter much less.
Epigenetic damage could potentially still be unfixable: how do you convince the thousands of different intermixed cell types in the body to all be the right type again? But Sinclair thinks the body already has a mechanism for doing this: epigenetic repair proteins called sirtuins. Sirtuin activity seems to be regulated by a protein called mTOR, which can be influenced by treatments such as rapamycin, an mTOR inhibitor. The other pill is nicotinamide riboside aka NR (and its close cousin nicotinamide mononucleotide aka NMN). The reactions catalyzed by sirtuins involve nicotinamides, and the more nicotinamides you have, the more effective sirtuins are.
People who are not David Sinclair generally don't expect conquering aging to be this easy. The anti-aging SENS Research Foundation has a list of seven different programs to address what they consider to be seven different causes of age-related damage. This seems more like the "humans are like cars" scenario where you have to fix every part individually and it's really hard. People who are not David Sinclair don't think that nicotinamides are a miracle drug. A well-regarded research center ran a big study on nicotinamides in mice and found that they lived no longer than usual, although they did seem to be healthier in various ways. And people who are not David Sinclair are less enthusiastic about sirtuins, mTOR, and calorie restriction.
My impression of the consensus in anti-aging research is that many people are excited for the same reasons Sinclair is excited, that people are much more optimistic than they were five or ten years ago - but that their level of optimism hasn't quite caught up to Sinclair's level yet.