Today's open access commentary is, I think, an overreaction to present challenges in engineering greater longevity via metabolic manipulation. I would be the first to say that altering the operation of metabolism is not a good path forward, at least if the goal is to engineer greater healthy longevity in our species. Cellular metabolism and its intersection with aging is ferociously complex and poorly understood in detail. Those details matter greatly: there are many feedback loops and switches based on protein levels that will change from beneficial to harmful for reasons that only become apparent after years of painstaking research. The best-studied mechanisms that link cellular metabolism to individual and species longevity have been under investigation for decades, and are still at a point at which related interventions are haphazardly beneficial and poorly understood.
Further, those best studied mechanisms, linked to the response to calorie restriction and other stresses, cannot greatly increase life span in long-lived species. They work quite well in short-lived species. That is well demonstrated: calorie restriction itself boosts mouse life span by as much as 40%, and certainly does not do that in humans. Thus we should not be looking to altered metabolism as a path that can add decades to the healthy human life span in the foreseeable future.
Arguing that this line of development is hard, and that all of the specific approaches examined so far appear to be capable of producing only low yields at best, in terms of healthy years added, is one thing. Arguing that it is impossible to ever achieve meaningful gains via this line of development is quite another. It is ridiculous to argue that it is impossible in principle to engineer humans to be very long-lived by changing the operation of cellular metabolism. We only have to look at the wide range of life spans in mammals to note that some concrete collection of differences must be enabling naked mole-rats to live nine times as long as mice, or for whales to live for centuries. Making significantly longer-lived humans through the approach of altered cellular metabolism is scientifically plausible - it just isn't a viable project at this time, and probably won't be for a lifetime yet.
This is why many people who have looked into the field in detail support the damage repair approach to rejuvenation, as first put forward by Aubrey de Grey and presently championed by the SENS Research Foundation and its network of allies and researchers. This is explicitly a strategy to work around the inability to make near term progress in altering metabolism. Instead we keep the metabolism we have, and target the periodic elimination of the various well-described forms of cell and tissue damage that cause aging. Remove the damage, and rejuvenation results, as illustrated in animal studies in which senescent cells are selectively destroyed via senolytic therapies.
The Zugzwang Hypothesis: Why Human Lifespan Cannot Be Increased
Lifespan is one of the most variable life history traits in the animal kingdom, lasting from days to centuries. Despite intensive investigation, there are still many grey areas in our understanding of the factors which contribute to the variability of lifespan. Humans are among the fortunate animals which have an unusually long lifespan compared to their similar sized mammals. On the flip side, the long lifespan of humans and large genetic heterogeneity are important reasons why it is very difficult to use humans as models to study ageing or longevity or test the efficacy of anti-ageing interventions. Ageing studies on humans often require a very large cohort of people and can potentially be affected by many confounding factors. As a consequence, most studies involving ageing, lifespan, and anti-ageing interventions are based on model systems.
In the evolutionary history after divergence from the great apes, the most recent of our primate ancestors, humans have completed almost 300,000 generations. During this period, the lifespan of H. sapiens has almost doubled. The increased longevity of humans is, in part, attributable to environmental changes; improved food, water, and hygiene; reduced impact of infectious disease; and improved medical care at all ages. However, the above factors had an opportunity to play some role in increasing lifespan only in the last 2 centuries. The dramatic increase in human lifespan compared to our nearest ancestors, should, therefore, must have other valid explanations. It is highly conceivable that forces of natural selection may have played vital role in increasing the basic longevity of humans.
Zugzwang is a German word with the literal meaning "compulsion to move." This word is frequently used in chess to describe a situation when a player gets a disadvantage because it is his turn to play, but all the available moves are bad. In Zugzwang position, any move the player makes will clearly weaken his position. Here, I propose that at this stage of evolution, humans may face the Zugzwang problem. Scientific research and the understanding of the hallmarks of ageing now provide humans with more than a dream to extend lifespan. However, it must be taken into consideration that natural selection has already played its part in extending human lifespan much beyond the expectation. All possible mechanisms which can increase longevity in lower animals have already been exploited by natural selection to stretch human lifespan. Any artificial attempt to tinker, through any possible intervention, with the signalling pathways or transcription factors to achieve a longer lifespan may actually be disadvantageous to humans.
Humans may thus be considered to be in the Zugzwang state. Humans may have already achieved or approached the maximum lifespan, and further lifespan extension may be very difficult or impossible. Documented record of human longevity for the last 100 years (with a conservative estimate of data from 8 billion individuals) shows that the limit of human lifespan is around 122 years; the fact that no individual has lived beyond this limit is a clue to the validity of the Zugzwang hypothesis.