LW - A primer on the current state of longevity research by Abhishaike Mahajan

Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: A primer on the current state of longevity research, published by Abhishaike Mahajan on August 22, 2024 on LessWrong.
Note: This post is co-authored with
Stacy Li, a PhD student at Berkeley studying aging biology! Highly appreciate all her help in writing, editing, and fact-checking my understanding!
Introduction
The last time I read about aging research deeply was around 2021. The general impression I was getting was that aging research was increasingly more and more funded (good!). Unfortunately, none of the money led to actionable or useful insights (bad).
Over time, you get slightly burnt out by all the negative news.
After getting a job in biotech, I kept a hazy eye on the subject but mostly tuned out of it entirely. But, especially today, I am curious: how has the aging field progressed in the last few years? Since 2021, what has changed?
In this post, I'll share a list of immediate questions about the state of affairs in aging research, and the answers I've found for them. For each question, I'll offer some basic background knowledge required to understand the question. Feel free to skip that part if you already understand the question!
Did the therapeutic focus on sirtuins amount to much?
Background
Sirtuins are a family of signaling proteins, commonly referred to by their corresponding gene name, SIRT1, SIRT2, all the way up to SIRT7. Their primary role is deacetylation, which is just the removal of a chemical marker (acetyl) on proteins.
It was noticed in the 1980s that some sirtuin classes were especially involved in three key activities: modifying histones, which are proteins that tune the accessibility of DNA in the nucleus, transcriptional modification, which determines how DNA is interpreted by the body, and DNA repair, which speaks for itself. And anything involved in modifying and maintaining DNA is something worth paying attention to!
Studies in the 2000s showed that the activity of specific sirtuin classes strongly correlated with age; the young had more sirtuin activity, and the old had less. This seemed to be causative in aging;
overexpressing certain sirtuin genes led to lifespan increase and
downregulation of them led to lifespan decrease. The results were a bit mixed, and the results were for yeast cells - always a red flag - but there was some promise in viewing sirtuins as an aging target.
It turns out that editing humans to safely overexpress sirtuin genes is somewhat hard to do (as is expressing any gene in humans). But there was an easy way around that: focus on molecules that are required for sirtuin to do its job. A class of therapeutics grew from this:
sirtuin-activating compounds.
How do you activate sirtuins?
Well, sirtuins are dependent on NAD+, or nicotinamide adenine dinucleotide, to perform their primary function. Increasing cellular NAD+ levels could also be a way to indirectly push for more sirtuin activity. Practically speaking, NAD+ bioavailability is poor, so supplementation with precursors to NAD+, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), was instead used.
There are plenty of other compounds in this category too: resveratrol, fisetin, and quercetin are all names you may hear mentioned.
How has this fared?
Answer
TLDR: The whole sirtuin theory was losing steam by the time I started reading about it a few years ago. It's only gotten worse. Nothing particularly useful has come from sirtuin-focused therapies, and likely nothing ever will.
A
Cell paper from 2018 found that NAD+ precursor supplementation didn't improve mice longevity. To be fair, they did show that supplementation improves some aspects of health-span, specifically improved glucose metabolism and reduced oxidative stress to the liver in aged mice, so still potentially useful. But nothing revolutionary.
Still, human clinical trials ...