Replacing Aging by Jean Hébert is the latest longevity book published for public consumption. While books such as these seem to be coming out more regularly, readers who have already tackled David Sinclair’s Lifespan, Nir Barzilai’s Age Later, or Aubrey De Grey’s Ending Aging shouldn’t simply dismiss Replacing Aging as something they’ve already seen. While Dr. Hébert is another scientist in the field of longevity who is decoding his research for the general public, he takes a much different approach to the field that interested readers likely have not seen elsewhere.
The case against drugs
Replacing Aging takes a heavily critical stance of the pharmaceutical approach most commonly employed by most longevity researchers. It only briefly skims over the motivation for fighting aging and counterarguments to common concerns about lifespan extension. As such, this book would not be a great medium to introduce people to the field, but others have already covered this in detail, and, as Dr. Hébert professes, it is not his area of expertise. Next, the book covers the processes of aging, including the different types of damage and the repair mechanisms that our bodies utilize in response. A major focus is placed on the sheer complexity of this system, which is shown to be staggering, based on what we do know, and potentially even more complex than that, based on what we don’t. This is the crux of the following, most controversial, portion of the book: why drug development won’t meaningfully affect aging.
There are many types of molecules in the body, multiple types of damage to each of those, and multiple ways of repairing each type of damage. Preventing or fully repairing one type of damage would not necessarily stop aging if other types were able to continue. The difficulty of targeting even one type of damage is also highlighted, with complex and tightly regulated molecular pathways at the center of each. Pathways usually overlap, sharing molecules with other pathways and making them difficult to modulate without off-target effects. Furthermore, many of these pathways do not simply turn on or off, but the magnitude must also be considered. Too much or too little expression of a molecule can result in a therapy that does more harm than good. Based on these arguments, it is not unreasonable to posit that all the “low-hanging fruit” in the world of pharmaceutical treatments have already been picked.
Alternatives to the pharmaceutical approach
The book then presents a competing thesis: replacement. Like a car, which can be driven indefinitely if its parts are replaced, the cells and tissues of our bodies may also someday be replaceable. Tissue engineering and regenerative medicine have made great strides since the turn of the millennium. Our ability to manipulate cells and manufacture tissues, while not yet reaching the clinic, has improved dramatically. Technologies such as induced pluripotent stem cells, bioprinting, and bioreactors may someday allow for lab-grown organs. The biggest hurdles in the way of replacement strategies are engineering problems rather than biological ones. However, there’s one big thorn in the side of this strategy, which also brings us to the focus of Dr. Hébert’s research: the brain.
As our thoughts and memories are contained in the brain, we would hardly be satisfied being replaced with a lab-grown brain. This is not a fatal flaw to replacement as a strategy, as much of the rest of the book covers the most promising research in replacing brain tissue in a way that would preserve our senses of self. The plastic brain is constantly remodeling itself as we form new memories and forget old ones. Removal of one part of the brain is remarkably compensated for by other regions. This slow replacement could occur on the macro scale surgically or on the micro scale through cell transplantation. The book concludes on more philosophical considerations, which demonstrate that it would be possible to preserve our senses of self while simultaneously making our brains younger.
Is drug development doomed to fail?
The drug development process is no stranger to criticism. Many other experts have made similar arguments over the years, although not usually in the context of lifespan extension. One ray of hope for longevity researchers has been that targeting aging may get at the underlying cause of many diseases and thereby succeed where the individual disease approach has failed. However, the possibility remains that drugs targeting aging will never be able to meaningfully extend the lives of patients or that they may only extend healthspan but not lifespan. The complexity of aging is one very real reason for this possibility. Replacing Aging highlights this prospect in a logical, well-written, and compelling fashion.
It is also a message that I believe more people need to hear. I did my PhD in tissue engineering but recently made a major switch to study cellular senescence in the brain. Because of this, reading Replacing Aging was deeply personal to me. It was a bizarre experience to read, as my new field was criticized in favor of the field I had just moved away from.
The future remains a mystery, however, and I found the certainty with which the book dismissed the pharmaceutical approach to be particularly flawed. The impression readers are left with is that success with drug-based treatments is impossible and that somehow we already know this without conducting clinical trials. We should not neglect recent innovations in drug development nor the possibility for future innovations. A lot can change in 10 years’ time outside the field of drug development as well, for example in artificial intelligence, which may impact its prospects.
In the same vein, the book fails to concede that replacement may also ultimately be an unsuccessful strategy. Replacement is not simply an engineering problem – it is a bioengineering problem. The same complexity that hinders the drug-based approach may prove too great for replacement as well. Additionally, transplanted cells do not fare well in an aged microenvironment. For example, transplanted organs quickly catch up to their hosts when old recipients receive organ donations from young donors. Further, older individuals do not tolerate and recover from surgery nearly as well. There is much we simply still do not know about which strategies can and cannot succeed.
Where do we go from here?
Ultimately, the most important question is whether the field needs to pivot in order to maximize the chances of successful treatments. In this respect, Replacing Aging crucially highlights the divide between tissue engineering and longevity research. Nearly all translational age-related research is focused on drugs. Similarly, nearly all translational tissue engineering research is disease-specific rather than aging-focused.
The National Institute on Aging (NIA) and the American Federation for Aging Research (AFAR) rarely fund replacement strategy projects. Tissue engineering is instead funded through a variety of other agencies based on individual diseases. This divide may be a major reason why tissue engineering researchers largely ignore aging. On the other hand, the research budget for aging is already miniscule compared to disease-specific approaches. The projects they currently fund do show significant potential, especially if we accept that we cannot predict what strategies will ultimately be successful. It is difficult to accept that we must divert precious funding from all drug-based approaches.
So, how much should we focus on drug-based or replacement-based approaches? Simply put, the longevity field needs diversity and as many shots on goal as possible. This means a greater incorporation of replacement strategies without a complete abandonment of drug development. It also means that the funding of “aging” research should not be not limited to the NIA. Since aging affects every system in the body, more divisions of the NIH should be funding these types of projects, making it a larger slice of the overall budget. Finally, we need to begin breaking down the silos between the tissue engineering and longevity fields. Dr. Hébert’s work is a sterling example of incorporating these two distinct but complementary areas. Hopefully, Replacing Aging will promote collaboration and encourage others to follow a similar path.