Earlier this year at the Undoing Aging conference in Berlin, I had the opportunity to listen to a debate between Dr. Vadim Gladyshev of Harvard Medical School and Aubrey de Grey of the SENS Research Foundation. The topic was “Is comprehensive damage repair feasible?”
What followed was a friendly and interesting discussion about the three main approaches that might be applied to aging in order to delay, prevent, or reverse age-related diseases.
From this discussion, we can divide the approaches towards treating aging into three broad categories.
Geroprotectors – The stopgap
There has long been an interest in mining the natural world for supplements and drugs that might slow down aging by boosting our innate repair systems or by slowing down the accumulation of damage. Such drugs and compounds that influence aging are known as geroprotectors.
There are an almost endless number of supplements for sale, many of which have sparse or dubious data to support their use in humans. However, there do appear to be some existing drugs and supplements that may prove useful for slowing down aging while more robust therapies are developed. Metformin and rapamycin are two examples of existing drugs that appear to influence the rate of aging to a certain extent and could potentially be useful as a stopgap before repair and rejuvenation therapies are available.
While it seems very unlikely that such repurposed drugs or supplements will greatly increase human lifespan, they may be enough to buy us additional time while better things are developed. More recently, AI has been utilized in the search for geroprotectors, and it is likely that more compounds will be identified that could help slow down aging.
Geroprotectors are something that we can develop in the short-term and they are immediately actionable; the only thing we need to do is separate the science from the snake oil, and AI is helping us to achieve this.
Another angle that Vadim rightly points out about geroprotectors is that success in this area could also serve to attract attention and funding while bringing in more talent to the field, thus having an effect considerably larger than the actual usefulness of a single compound that is found to work.
We should probably not put too much stead in geroprotectors, but before we have better technologies at our disposal, they may prove useful.
Repair – Divide and conquer
SENS proposes to directly repair the damage caused by the various aging processes, which its model has divided into seven categories of damage. The idea behind approaches such as SENS is to periodically go in and repair the damage that aging causes in order to prevent it from reaching pathological levels and leading to the ill health of old age.
The SENS approach has proposed solutions for dealing with each of the damages that it considers to cause aging, such as clearing harmful senescent cells, which accumulate with age and drive chronic inflammation and the decline of tissue repair, along with replacing populations of specialized cells in various organs.
The analogy of a car is often used when describing the damage repair approach; through periodic repair and maintenance, it’s possible to keep a car on the road far longer than its manufacturers planned, and SENS applies the same logic to the human body.
Whether or not this preventative and periodic repair approach will be enough is the subject of debate; however, a number of repair-based therapies are now in human trials or quite far along in development; hopefully soon, we will start seeing data from these studies. The idea behind the periodic repair of aging is scientifically plausible, and, after decades of work, are finally looking like a real prospect in the next decade or two.
Rejuvenation – Resetting aging cells
Another possible solution is the rejuvenation of cells using approaches such as cellular reprogramming, in which cells’ age is reset using reprogramming factors. The plausibility of this approach is exemplified by induced pluripotent stem cells (IPSCs), which are aged adult cells that have been reprogrammed so that their age is reset.
However, IPSCs are fully reprogrammed in this process, and not only do these cells lose the markers of aging, they also forget what specialized cell types they used to be; they have reverted back to pluripotency, an embryonic-like state in which they can change into any other cell types, just like they do as we develop as babies.
Obviously, we do not want our bodies’ cells to forget what they are when given a therapy, so the solution is to partially reprogram the cells to remove their aging markers but not to deprive them of their identities.
Fortunately, this seems to be a plausible approach, as the aging markers are removed from cells before their identities are erased; therefore, it is possible to expose cells to reprogramming factors just long enough to achieve this partial reset, and this approach has already increased the healthy lifespan of mice .
Vadim considers the angle of damage dilution, in which cells simply divide to reduce damage and accumulated waste. Partial cellular reprogramming holds a great deal of potential, and Vadim suggests that because of the damage dilution effect, it deals with damage in its entirety when it makes the cell function as a young cell again. Each time the cell divides, it effectively exports its waste and damage to daughter cells. For example, each time a cell divides, insoluble waste such as lipofuscin is reduced by 50%. Therefore, rejuvenating our cells in this way may help dilute accumulated damage.
There are some hurdles to overcome in regards to using partial reprogramming in humans, but there are multiple companies working on this, including Agex, Turn.bio, Life Biosciences, and Youtherum. If partial cellular reprogramming can be perfected and solutions found to replacing non-dividing cell populations, this has the potential to be transformative for aging and the treatment of age-related diseases.
It seems clear that all three of these approaches to aging have their place. It remains to be seen how effective direct damage repair will be compared to reprogramming and dilution; however, it may be the case that both repair and reprogramming will ultimately be used together as an all-around solution to aging.
Repair approaches could potentially replace populations of non-dividing cells, such as the specialized neural stem cells found in the hypothalamus, which regulate hormones and some aspects of aging. They may also be a solution to dealing with damage that cells likely cannot dilute because they exist outside the cells, such as crosslinks and other waste that our cells cannot deal with.
Of course, we cannot say for sure how things will pan out in the future, and it will likely be some decades before we reach this point, so this is merely speculation. We certainly agree with Vadim when he concluded that all three approaches are valid and should be pursued, and we would like to thank both researchers for providing such a thought-provoking discussion.
 Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, Roman JLXJ, Rodriguez-Esteban C, Nuñez G, Nuñez Delicado E, Campistol JM, Guillen I, Guillen P, Izpisua Belmonte JC. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell. 2016;167:1719–33.