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.
dysfunction of the neurmuscular junction is probably the most important type of muscle aging, much more so than cell loss
Good answer, but I disagree with this specifically. I spent a few days reading up on age-related NMJ dysfunction at one point, and my main takeaway is that it’s widely studied mainly because it produces cool images. I have not been able to find any evidence at all that NMJ problems cause age-related loss of muscle strength, despite the large amount of research poured into the subject. (If anyone knows of such evidence, I’d love a link to it.) My current best model is that age related NMJ remodelling is just a side effect of other damage/repair, and doesn’t have much functional impact other than making the junctions look a bit different when people image them.
I thought the idea of the hallmark was that there was one thing that you could fix and if you fix it then you solved the issue.
If you solve stem cell aging you don’t automatically get more muscle cells.
You might, at least if the intervention is preventative.
(Sorry in advance if this is all review...)
Muscle cells are not like most other cell types. A single muscle cell is more like a giant conglomerate of a bunch of cells, all merged within a single membrane. There’s many nuclei in each muscle cell, many full sets of chromosomes, and the cell is big enough that most proteins will never diffuse from one end to the other before turning over. Unlike normal cells, the nucleii themselves can turn over independent of the cell—and muscle stem cells (“satellite cells”, the first type of stem cell discovered IIRC) are primarily responsible for this turnover.
Now, at this point we don’t know for sure if satellite cell problems are the primary driver of age-related muscle loss, but they’re definitely one of the top candidates (mitochondria are another). And if that is the main driver, then fixing stem cell aging would indeed fix muscle loss—not necessarily retroactively, but at least preventatively.
The main takeaway here is that, while individual muscle cells are long-lived, their components still turn over. There’s probably something upstream of muscle loss which drives it.
Replenishing nucleii in established muscle cells doesn’t replace dying muscle cells. It might very well be that part of age related muscle loss is not due to lower count of muscle cells but due to other factors but sometimes muscle cells will die and that will produce muscle loss as people age when those aren’t replaced.
Cells die for many reasons. I don’t think you should expect zero muscle cells to die for any reason even if you help them replenish their nuclei.
My understanding is that muscle cells don’t just randomly die fast enough to account for age-related muscle loss. In young people post-development (i.e. people in their 20′s or early 30′s), it’s quite slow. Then with age, it accelerates. Fix whatever’s causing that accelerated loss, and muscle loss would be basically negligible.
What does “negligible” mean here? Negligible on what time scale? Because if the overarching question is “How do we stop or reverse aging to become amortal?” then any process of monotonic irreversible decline becomes important eventually.
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.
Aubrey’s case for trying to focus on the hallmark is that there are a lot less of them then illnesses and it’s thus easier to focus on hallmarks then on illnesses.
It seems that this thesis is basically wrong if they are two vague to be individually targeted.