u/dan_in_ca

A review on how SGLT2 inhibitors target ectopic fat (specifically epicardial fat). Ectopic fat is the excess fat that gets stored in organ tissue. The paper outlines the different mechanisms of how it does so. For anyone not familiar with SGLT2 inhibitors, they cause you to urinate 60-80g of glucose, so it can cause a mild caloric deficit. It would be interesting to see a side by side comparison of how SGLT2i's compare to GLP1 reduction in ectopic fat.

For anybody interested in the metabolic hypothesis of Alzheimer's, this is an interesting overview of research on the overabundance of glycan protein modifications and the failure to clear them as contributors to Alzheimer's pathology.

One of the more interesting callouts was glucosamine usage was associated with a 25% higher mortality risk in patients with established Alzheimer's disease-related dementia, and a 25 percent higher rate of progression from mild cognitive impairment to full dementia.

Major caveats are needed to process that finding because it seems like this finding does really translate to healthy people taking glucosamine. The biological mechanism through which it could worsen outcomes in an already hyperglycosylating brain is coherent though.

An analysis of a new biological age model from the Wyss-Coray Lab at Stanford. Bioage models typically give a composite number. This model maps aging at the level of individual cell types, 40+ simultaneously from a single blood draw. It's validated across two proteomics platforms and with blood bank data from 60k people.

The big takeaway is that it has a disease prediction model. Extreme astrocyte aging predicted Alzheimers with a hazard ratio comparable to APOE4 over 15 years. Extreme skeletal myocyte aging predicted ALS 12.7x higher risk years before diagnosis. And people with extreme aging across 20+ cell types had 34% 15 year survival vs 90% for normal agers. Pretty cool if true.

Caveats are real though. The proteomics platforms aren't routine clinical tools yet, cohorts were mostly older and caucasian, and nobody has shown that actually modifying these cellular aging trajectories changes outcomes the way the associations predict. But the idea that you can get cellular resolution biological age from a blood test and meaningfully improve disease prediction over composite scores feels like a step forward. Cautiously excited about where this goes as the tech gets more accessible.

I follow Dr. Englund on Twitter. His lab did put out a review on senescence as a driver of muscle decline. He did an interview on his research. I think one thing for this community is that it is clear that muscle is a longevity organ. Specifically, not just as a place to deposit glucose, but as an endocrine organ secreting myokines, which seem to have a bunch of longevity benefits.

His argument is that senescence is one of the primary biological threats to muscle quality with aging. From the video, he's making the case that senescent cells accumulate in muscle fibers and suppress satellite cell function, which is needed for muscle function and growth. In his research, he showed that you could give mice the senolytics dasatanib and quercetin and preserve muscle fiber size. There's also some cross-species validation in human muscle samples. The human trials were very small, and there are no dosing guidelines for humans. So anyone thinking they could try dastanib, it's probably not a great idea.

Obviously, they talk about rapamycin, not as a senolytic, but as a senomorphic and also increase mTOR sensitivity (not the main topic though). The other dynamic was that resistant training had a senolytic effect as well.

Curious if anyone here has a senolytic strategy. Fisetin + Quercetin? Anyways, wanted to share this video as I thought it would be of interest here.

Interesting concept. While I think sympathetic overdrive is a contributor of aging and a propellant of the hallmark of aging cascade, I am not sure it’s the singular driver. It’s a provocative theory nonetheless. The authors suggest that interventions that target parasympathetic tone are longevity interventions. More reason for recovery. But this is just a perspective paper, not an actual experimental study.

Curious what people think of HRV as an aging biomarker.

Interesting take on the amyloid hypothesis of Alzheimers vs a metabolic framing. The Alzheimer's research I find most compelling lately isn't about amyloid clearance. I've been interested in the upstream drivers of amyloid. Specifically, the mitochondrial dysfunction that drives neuronal death and inflammation.

This is an interesting read because it points to a paper that dissects how defective mitophagy precedes plaque formation. They tried to restore neuron function by restoring mitophagy through urolithin A and an antioxidant EGCG. I think there are a number of ways to increase mitophagy that do not involve taking compounds, but the thing that was interesting was that when they restored mitophagy through these compounds, the results improved every level of the disease cascade (neuroinflammation, synaptic health, energy output, and most importantly amyloid), implicating mitochondrial dysfunction and defective mitophagy specifically as an upstream driver of the pathology and the plaque formation.

The thing to be most skeptical about is that it is a mouse study. Mechanistically, it makes sense. Anyone who is familiar with the field knows that there is a huge translational gap between mouse Alzheimer's models and human disease pathology, which has burned the field before. What is worth noting is that this study used a more realistic mouse model than most, one that lets human amyloid accumulate gradually under normal regulatory control rather than through genetic overexpression of familial mutations. Still a mouse, but a more honest one.

Anyone utilizing mitophagy stimulating strategies for cognitive health?

Posting this here because of its longevity implications. The paper is really about a textbook aging hallmark showing up early, visibly, and reversibly in human tissue, and then getting tested against an actual clinical endpoint, which we almost never get.

The setup: the ovary ages faster than almost any other organ, so it's a useful early-warning window into processes that hit the rest of us more slowly. The study ran multi-omics on human oocytes and their surrounding support cells across age, and found a sharp molecular inflection around 34. Basically protein synthesis and ribosome gene expression climb while autophagy declines. There's a dynamic where the cell's quality control (autophagy) cannot keep up with its growth output...then leading to a decline in the function.

They did low-dose mTOR inhibition through rapa and this protein activity normalized and autophagy was restored. The overall functional measurement was that IVF success rates went from 28% in the control group to 50% in the mTOR inhibitor group.

Where I'd stay skeptical: it's a single trial, n=100, single tissue, and "clinical pregnancy" is not live birth, which is the endpoint that matters. The mouse and cell work is mechanistically tidy but tidy stories invite confirmation bias. The age-34 inflection is correlational against the demographic curve. Columbia's Zev Williams lab has a parallel trial (Vibrant) worth tracking for replication.

Mostly curious what people make of using the ovary as a fast-forward model for systemic proteostasis collapse, and whether the intermittent low-dose framing here maps onto what folks here actually do.

Interesting data on NAD levels with age. Just to give everyone a heads up this is not specifically about precursors (NR or NMN). The Nature paper did an analysis of NAD+ levels as we age. The background was that they suspected that there were some methodological issues with the way previous studies measured NAD levels that showed a decline with age..

They created seven cohorts with a total of 700 participants. NAD+ levels did not decline with age, and did not differ between elite athletes and sedentary groups (a genuinely surprising finding).

They did find that NR supplementation did increase NAD levels. Basically, raised NAD levels beyond a normal baseline and not correcting a deficit.

They tested the old methodology of previous papers (which showed a decrease in NAD levels), which tested frozen blood samples. Freezing blood before measurements degrades NAD levels 21-27%. Essentially, it disrupts the red blood cell membrane and exposes the NAD to enzymes that degrade it. The conclusion is that previous studies which froze samples, made it seem like there was a decline due to aging, when it was just a methodological problem.

On one hand the animal data supporting NAD+ biology is real. This study only looked at blood, not muscle or liver or brain where the interesting aging biology actually happens. On the other hand if the biomarker people have been using to track whether their NR or NMN is working doesnt actually track aging, that seems worth knowing.

Has anyone been tracking it longitudinally and found it useful or not?

I have been reading more about the evolution of blood-based biological age models. It seems like there is some progression from Levine PhenoAge to the Bortz model, and Matt Kaeberlein and Brian Kennedy have developed their Lineage model. Boortz was developed on UK Biobank data from over 300,000 individuals.

The newer models are making more claims about the direction the individual is making across various systems and how quickly. If accurate, that seems useful.

A few things I am genuinely curious about from this community:

Is anyone here actually tracking biological age longitudinally? If so, which model are you using and have you found it responsive to interventions you have made?

The fasting insulin argument seems interesting. Most panels focus on glucose and HbA1c. Has anyone here pushed their doctor to include fasting insulin in routine panels and found it useful?

The cystatin C versus creatinine debate is interesting for anyone doing resistance training or using creatine. Has anyone switched to cystatin C for kidney function assessment and found it changed their picture meaningfully?

More broadly, do people here think blood-based biological age models are ready for serious clinical use, or are they still primarily research tools? I am curious whether people who follow this space closely find the outputs actionable or mostly interesting in principle.

Came across a review of Boortz. Sharing in case it is useful for the discussion.

Interesting review on GLP-1s and neuroprotection/dementia. Obviously, some of the longevity benefits have to be mediated through the caloric restriction dynamics of being on these medications. The dementia data is kind of a mixed bag.

The case for its neuroprotective benefit seems to largely come from epidemiological studies. A "retrospective cohort of over 295,000 patients found GLP-1 use associated with about a 70% lower risk of incident dementia versus non-use." The other data points come from 3 randomized cardiovascular trials, which showed a 53% lower dementia rate in patients randomized to GLP-1s versus placebo. So, it's a pretty big signal there from epidemiological studies. Would you get the same from other caloric restriction measures? I don't know, but caloric restriction is hard to adhere to for long periods of time.

From a mechanism angle, once again, it theoretically comes down to the distribution of glp-1 receptors, and in this case, GLP-1 receptors in the brain. "GLP-1 receptors are expressed on up to 70% of cerebral aterioles," according to the article. The implication is that glp-1s improve cerebral blood flow, which fits a vascular hypometabolism hypothesis of Alzheimers that some forms of dementia are at least partially driven by a chronic failure of blood flow and energy delivery to the brain. This is the case where the purported benefits are independent of caloric restriction and the weight loss effects of these meds.

The case against would be the recent EVOKE trial. Specifically, oral semaglutide seemed to fail the endpoint of the trial of slowing down cognitive decline. Maybe the oral delivery wasn't strong enough? thoughts here? It would be interesting to see the trial replicated with injectable sema or tirzepatide, to see if it has higher brain penetration, and to see if that is at least one variable that led to the poor outcome.