Here's a quick summary of interesting things to understand about aging biology, if you're new to the field:

There are multiple, different definitions of aging. There are definitions around time (stuff that happens as you get older), around function (stuff that breaks down as you get older) and causality (stuff that makes you break down as you get older) (2/n)

Historically, we mostly studied the first and second things. The big shift in ~1930s (caloric restriction) and ~1980s-onward were findings around causality (what might be causing this and can we fix it?)

We don't know how aging works or why it happens. We really aren't at even a Newton-level understanding of the process (Newtonian = 3 fundamental laws of physics). But, we do have a lot of very interesting leads. Example things are caloric restriction, insulin/IGF-1 signaling, etc

Caloric restriction was one of the first things people found to affect aging. It was interesting because it produced an opposite effect to what you might assume (starving rats might seem unhealthy, but it made them live longer). This was discovered ~1930.

We now know the story is a lot more complex than just 'eat less, live longer'. Careful studies have shown that decreasing just protein (in mice!) leads to lifespan extension, potentially through a signaling pathway.

Caloric restriction studies also have lots of problems (mice might not live longer at other temperatures, or they might be abnormally housed in a way that CR fixes, but isn't reflective of humans).

Tbh, I think nutrition is probably the hardest longevity thing to study b/c it's like a bajillion molecules at unknown proportions you're injecting into the system at once. Why on earth would that be simpler than studying a small molecule or biologic?

I mention CR first because historically it came first and people talk about it a lot. But the thing I'm most interested (the next major wave of work) came in 1983-1993 with the discovery that genes can control aging (9/n)

What does that mean? Well, it means for some reason animals are programmed to be able to modulate their lifespan. Not obvious to what extent, but there's biology there. That's a whole subfield of aging, and started with the insulin/IGF pathway. (11/n)

There are lots of caveats to this. There are no immortality genes we know about. This hasn't literally translated to humans yet. But we are pretty darn sure you can make a bunch of animals live longer by mutating the same kind of gene. We've done hundreds of these studies. (11/n)

This discovery kicked off a whole field of aging biology, hunting for new pathways that can control lifespan. Other pathways discovered include mTOR (what rapamycin drugs), sirtuins (not as large an effect), autophagy pathways, and dozens of others (12/n)

Each of these pathways is now the seed for a new field, and some have also been targets for expanding areas of drug discovery (rapalogs, sirtuin activators, etc) (13/n)

Interestingly, some of these pathways were *already* studied for their relevance to age-related disease (for example, FGF-21 over-expression in metabolic disease). We just didn't know they could also make mice live longer. (14/n)

Other subfields have come to prevalence by different paths. For example, Nobel laureate Alexis Carrel kicked off the field of parabiosis in early 1900s with various suturing and transbiosis techniques. It was mildly explored in longevity in the 1900s (15/n)

In 2005, the Rando lab at Stanford published work looking at muscle regeneration under parabiosis. In 2014, groups including Villeda at UCSF expanded on this work by looking at different tissues (16/n)

However, as far as I know, there's not one good parabiosis longevity study showing young blood or parabiosis to a young animal increases lifespan. There's one sketchy one everyone cites, but it's not stat sig (I think). So that's still tbd. (17/n)

Also, we already know some circulating factors that when increased or knock down have very strong longevity effects. I'm not sure how often those are re-discovered in parabiosis screens, but I'm confused it doesn't happen more often, as the effect sizes are very large. (18/n)

Senescent cells are another subfield - they were originally discovered in the context of 'why do cells stop dividing after ~50 divisions in culture?', and are now a kind of cell we think, when eliminated, might produce strong rejuvenation effects in mice (19/n)

However, we don't really know what these cells are. I mean to the extent we know what a cell type is (antigens on the surface? Gene expression profile? Having isolated it from a specific place in a mouse?). The gene senescence markers we have aren't obviously that specific (20/n)

There are various theories about why senescent cells are bad, usually to do with some kind of inflammatory profile they secrete which you want to get rid of. To my knowledge, we don't have causality on this mechanism in humans yet (21/n)

There are also now a lot of companies trying to drug senescent cells (small molecules, antibodies, gene therapies even) on the way to the clinic. The 2011-papers on it were compelling enough to spark that activity. (22/n)

I'm most interested in aging fields that don't fit into the above paradigms, or that come from decades of investigation in other areas. In the field, in genetic pathways that control aging because it's so weird that they exist. Also, they have nice modularity to drug. (23/n)

I think one contentious point in aging biology has been assuming it's easier to directly get rid of damage directly than to used evolved pathways to do it, if they exist. Of course, if they are limited in scope, the former approach is necessary to make a big dent in healthspan.