The sad fact is that we do not even understand mice very well. There is this old joke that can be paraphrased like this: if I were a mouse I could be cancer free and live forever, because it is so easy to cure these guys of diseases. As it turns out, however, this is not true. Within my field it was long gospel that caloric restriction (discovered some 100 years ago) can robustly extend mouse lifespan until studies in the last 20 years called this into question.
What the joke gets right is that we understand humans even less than mice. In fact, despite the controversies several interventions are relatively robust in mice when it comes to extending their life and health span (rapamycin, caloric restriction, growth hormone loss) while the evidence in humans is much weaker for these.
Delivering useful drugs, hopefully faster not slower than in the past, despite these issues will be an interesting challenge.
I guess this goes back to the issue of defining things and what you mean by hallmarks. If you define your hallmarks broadly enough they may include almost anything while being so vague that they are only useful for posters and ads. In the case of vague hallmarks you’d be right, if you fix them you’re all good. But even in this extreme case I do expect the number of vague hallmarks to grow a little bit over time as we learn more. In fact, to me they feel incomplete and ill-defined already.
Looking at the classic “The Hallmarks of Aging” paper (first published as López-Otín et al. 2013 I think) or Aubrey’s seven causes of aging I do feel like they are way too vague. Let’s take genomic instability as an example. Fix it and you make progress against aging. However, that is just an empty phrase like “repair the engine of the car”; that’s usually the reason why it stops in the middle of the highway. Which genome, mitochondria, nuclear? Which pathway do you target? Hundreds of genes involved in repair, hundreds of genes involved in prevention of DNA damage via the intricate ROS- and stress-sensing pathways. Which type of lesion to prevent? Damaged bases or strand breaks? Which type of existing damage to repair and remedy post facto? Actual mutations (not just temporary damage), small indels, aneuploidies, large deletions, inversions, translocations or more complex chromosomal rearrangements and clonally expanded cell populations? Don’t forget to fix chromatin organisation and epigenetic marks and all the inter-related extra-nuclear factors that promote genomic instability (could be inflammation, could be reduced autophagy, let’s speculate). Want to use nanobots instead? Be my guest, then you are solving advanced physics, engineering and AI problems.
Regarding incompleteness and definitions: Why did they choose to define telomere attrition as its own hallmark? First of all, this is an incredibily specific problem and secondly telomeres are part of the nuclear genome, i.e. they fit entirely within the scope of genomic instability. On the other hand, extracellular matrix aging is not part of The Hallmarks even though it has been suggested to be a life-limiting pathology since the early 20th century with good supporting evidence (think vascular aging).
As you can see these Hallmarks are a political, strategic and scientific compromise. (One can guess telomeres are on there because of the Nobel prize, public perception that they matter or some telomere researcher on the paper.)
However, I do see the appeal of these words, hallmarks, causes, even if their use in practise is limited.
My reply comes a bit late since I managed to write a long comment without clicking send and only noticed this now. I will address the errors I see in the TL;DR summary from the POV of a semi-professional biogerontologist:
The disease-based approach to aging this seems to favour is useful, but limited. In fact, if you genuinely want to extend both lifespan and healthspan this excessive focus on the disease-based approach would be inefficient because is inconsistent with everything we know about aging. I would go as far as to say that the disease-based approach may be actively harmful because it takes away resources from genuine aging research.
While aging probably has thousands of causes, or even more*, this does not preclude the existence of major causes that limit lifespan in the near term. This idea has been popularized by Aubrey de Grey a long time ago and now has reached the scientific mainstream with an emerging consensus about the Hallmarks of Aging (several key pathways and sequelae of aging). We also know that this view is decently well supported in mice and have known so since the late 1990s when Holly Brown-Borg and Andrzej Bartke introduced the Ames dwarf mouse to gerontology. If aging was strictly multifactorial and polygenetic there would be no hope to identify single genes that lead to pronounced lifespan extension, as they did with the long-lived Ames mouse, which is long-lived because of an underdeveloped pituitary and reduced growth hormone levels. This means one simple change to a single pathway can extend lifespan.
Of course, I am biased, since as a biogerontologist I think the biggest gains are to be had from targeting aging directly, although we can have a discussion how well the mouse data translates to humans. (Not well, IMHO, but it is the best we have.)
Sizable lifespan extension we have seen in mice has come, without exception, from interventions that target aging directly through the above discussed “hallmarks”. Just to give three famous examples of life extending treatments: We have Rapamycin, an inhibitor of the mTOR pathway, that became a plausible candidate after this pathway had been implicated in the aging of yeast. Then we have caloric restriction, which was discovered by accident and not by the disease-based approach, but is now known to target a global pathway that promotes tissue maintenance under nutrient stress. Finally, we also have senolytics, drugs that were developed to kill senescent cells, that had been linked with aging after decades of biogerontologic research.
In contrast, drugs like Aspirin, Simvastatin, Enalapril and many others were tested in mice with no clear biogerontologic rationale behind them and predictably failed to extend lifespan, even though they are obviously amazing from a disease-prevention point of view.
However, I do agree that biogerontology depends on the existence of a strong biomedical ecosystem. Rapamycin was initially discovered as an immunosuppressant and if not for that, it would have taken longer to find inhibitors of the mTOR pathway (but eventually it would have happened by standard medicinal chemistry). Working in the 1930s Clive McKay, the discoverer of caloric restriction, was perhaps more interested in the basic biology of starvation and malnutrition than finding treatments for aging, etc.
Nothing about age-related multimorbidity makes sense if it not viewed through the lens of biogerontology.
Notes* for example, you may be able to get 10-30% of lifespan extension by targeting the top 10 causes of aging, then eventually as you want to extend lifespan more and more, other causes of aging would take the spotlight
Actually, they all do include it, but is is subsumed under stem cell aging, loss of cells and reduced regenerative capacity. Also to clarify what I would consider a misunderstanding. Not everything has to fit. There are probably infintely many causes of aging or at least quite a lot. Most of these fall into the rough categories or “hallmarks” we have come up with like reduced stem cell functioning or damage to biomolecules. Many of these causes are not relevant to immediate life extension which is why they can be ignored for now. Other categories or “hallmarks” will be discovered as we go along.
Having said that, dysfunction of the neurmuscular junction is probably the most important type of muscle aging, much more so than cell loss, and, being so complex, I do not think the hallmarks do it much justice. Many of the hallmarks are so vague as to be almost useless anyway.
Does not make that much intuitive sense to me because there are a lot of random mutations happening. If the first dose first (or first dose only) strategy reduces the size of the whole SARS-CoV-2 viriome, there will be fewer viruses and less genetic variation in total. More infections in total means more genetic diversity. More infections means that a vaccinated person will be exposed to more sources of infection, more virions, more different genomes over time, thus also increasing the likelihood of mutants able to escape the immunologic response.