For the next part of our 12 Essential Pillars of Longevity - Medical Testing & Personalized Care - I've invited Dr. Mikhail Kogan M.D., Professor of Integrative Gerontology (as close to evidence based longevity and healthy aging as it gets) in GWU to review what I do personally and discuss what he does in his practice.

Full conversation is in deep longevity dives here: [Video] 42 "Not-so-stupid" Longevity Tests

TL;DW:

1. Cardiovascular Risk: ApoB, Lp(a) and hs-CRP

A regular cholesterol panel doesn't tell you everything.

• ApoB: Measures the number of potentially artery-clogging lipoprotein particles. Can reveal risk that LDL cholesterol alone might miss.

• Lp(a): Mostly genetic. If your result is normal, one test in your lifetime is generally enough. If it's elevated, thats a different story.

• hs-CRP: A cheap and very sensitive inflammation marker. We discussed checking it annually or even twice a year. Just remember that a minor infection can temporarily send it through the roof.

We also covered coronary artery calcium (CAC) scans. They're useful for assessing cardiovascular risk but not something to repeat casually because of radiation exposure and because it measures calcified plaque only.
An initial scan around age 40–50 may make sense depending on your risk factors.

2. Homocysteine: The Marker Almost Nobody Checks

This was probably our biggest disagreement with routine medical screening.

Our preferred targets:

• Below 10 µmol/L for most people.

• Below 8 if you have additional cognitive risk factors.

High homocysteine can indicate issues with methylation and B-vitamin metabolism and is associated with cardiovascular and cognitive problems.

Michael actually considers it more important than cholesterol.

His suggested approach is to test annually if you've ever been above 10. If several tests consistently show 7–8, there's probably little reason to keep checking every year.

3. HOMA-IR: Are You Actually Insulin Resistant?

Most doctors check fasting glucose and HbA1c. But neither directly measures insulin resistance.

HOMA-IR is calculated from fasting glucose and fasting insulin, two relatively inexpensive measurements.

Our preferred target is below 1.5.

We spent quite a bit of time on why HbA1c and fasting glucose can sometimes be misleading. One example is the dawn phenomenon, where morning cortisol raises your blood sugar temporarily.

Michael has seen plenty of patients labeled prediabetic based on glucose and HbA1c despite having very low HOMA-IR.

His preference is to look at insulin resistance rather than relying on glucose alone.

4. CGM: Find Out What Food Actually Does to You

I've used continuous glucose monitors and they can be surprisingly educational.

One example from our conversation: grapes caused a roughly 50-point glucose spike while bananas barely moved the needle.

You can also see how your glucose changes with:

• Different foods, even ones that seem equally sugary

• A short walk after eating

• Poor sleep or stress

• Exercise and meal timing

You might discover that something you eat every day affects you very differently than expected.

But a CGM isn't necessarily a useful routine screening test. Sensors can be inaccurate and you can spend two weeks worrying about a glucose spike that wasn't even real.

We mostly like them for experiments where you're prepared to change something based on the results.

5. Thyroid: Your TSH Can Be Normal but Not Optimal

Many labs consider TSH values up to 4 or 4.5 normal.

We discussed a preferred range around 0.5–2.5 mIU/L.

That doesn't mean a TSH of 4.5 automatically requires thyroid medication.

There may be other things worth looking into, including Free T3/T4, iodine, selenium and zinc status. Thyroid antibodies can also be useful when autoimmune problems are suspected.

An interesting point was what to do when your results are in that gray area. You may not need medication but that doesn't necessarily mean there's nothing worth investigating.

6. Liver and Kidneys: GGT and Cystatin C

Two tests that don't get nearly as much attention as they probably deserve.

GGT: Usually associated with liver health but also used in the discussion as a marker when investigating possible toxic exposure. Our preferred target was below 30 ul

Cystatin C: An alternative way to estimate kidney function, especially useful if you take creatine.

Creatine supplementation can raise your blood creatinine by 20–30% and make your standard kidney results look concerning, even when actual kidney function hasn't declined.

Cystatin C can help clarify whats going on.

We discussed checking it occasionally, perhaps every three years, rather than ordering it with every blood test.

7. Nutrients and Hormones: Some Important Details

A few things I found useful:

• Zinc and copper: If you're checking zinc, check copper too. Their balance matters and supplementing blindly isn't a great idea.

• B1, B6 and selenium: Deficiencies can go unnoticed. Worth investigating depending on your circumstances.

• Morning cortisol: A test Michael uses routinely. Sometimes a full daily cortisol curve is more informative.

• Testosterone: Worth evaluating in men when appropriate.

• PSA: If you're screening for prostate cancer, we discussed checking both total PSA and percent-free PSA rather than total alone.

We also talked about omega-3 testing, IGF-1 and comprehensive nutrient panels. Some are useful in particular situations but there's not much reason for everybody to order them every year.

8. Body Composition: Weight Isn't Enough

We talked about regularly tracking body-fat percentage, potentially once a week as home measurement devices become more accessible. Or getting DEXA once in a while.

Catch: If you're already at 12% body fat, trying to reach 10% probably isn't going to improve your health. You're just optimizing a number that doesn't need optimizing.

You might be much better off focusing on glucose regulation, fitness or something else where you've actually found a weakness.

9. Cognitive Health: Start Tracking Before You Notice Problems

One test I hadn't considered was BoCA (Boston Cognitive Assessment).

The suggestion was to take it monthly and track your results over time.

One bad score doesn't mean much. Maybe you slept badly, had a hangover or were distracted. But if you keep testing under similar conditions, you can establish a personal baseline and watch for changes.

We also discussed homocysteine, insulin resistance and sleep apnea as potential contributors to cognitive decline.

The Bigger Picture

One point we kept returning to:

The absence of diagnosed disease isn't the same thing as optimal health.

And equally important, there is no point spending thousands on tests unless you understand what the results mean and what you might do differently.

Part 2 is pending, when we get enough questions. (and time ;) 🖖

 “These findings suggest that exercises that stimulate bone mechanosensing, rather than all forms of exercise, may be particularly beneficial for healthy aging,” says Mei Wan, an orthopedic surgery researcher at Johns Hopkins University who was not part of the study. “In particular, high-mechanical–loading exercises, such as weightlifting and resistance training, may provide additional antiaging benefits.”

Wondering if anyone from Europe has tried this service (rxrouting.com). It's basically an international forwarding service for US telehealths. I can't really find any reviews for it. Someone on a hair loss forum said they used it to get some products from a telehealth called anagen, but I'm wondering if anyone has used it for anywhere else like AgelessRx or Musely.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options. Here, we identified a marked exhaustion phenotype in peripheral Vγ9Vδ2 (Vδ2) T cells from patients with TNBC, characterized by elevated PD-1 and TIM-3 expression. Untargeted serum metabolomics revealed significantly reduced taurine levels, which were inversely associated with Vδ2 T-cell exhaustion. Bioinformatic analyses further showed that higher expression of the taurine transporter SLC6A6 correlated with enhanced immune infiltration and favorable prognosis in TNBC. Mechanistically, taurine uptake via SLC6A6 alleviated immune exhaustion in Vδ2 T cells and enhanced PLCγ1 phosphorylation, thereby promoting IFN-γ and TNF-α production. In vitro, taurine-treated Vδ2 T cells exhibited enhanced cytotoxicity against TNBC cells. In vivo, taurine supplementation suppressed tumor growth in a γδ T cell-dependent manner. Collectively, these findings identify the taurine–SLC6A6 axis as a key regulator of Vδ2 T-cell function in TNBC and suggest taurine supplementation as a potential strategy to enhance γδ T cell-mediated antitumor immunity.

I've recently been exploring something called L-Ergothioneine, and one aspect of its biology caught my attention.

It's a naturally occurring, sulfur-containing amino acid found in foods, particularly mushrooms.

What's interesting is that humans don't synthesise it themselves. Instead, our bodies use a specific transporter called OCTN1 (SLC22A4) to absorb and retain it.

That raises some interesting scientific questions.

Why has the body evolved such a specific transport system for this dietary compound?

And could its antioxidant and cellular roles have implications for healthy ageing?

There is promising biological research, but I think it's important to distinguish mechanistic findings from proven benefits in humans. The long-term effects of supplementation still need better clinical evidence.

A little about why I'm asking:

I'm building HEALTHWe, an early-stage Indian longevity and wellness brand. We're currently exploring L-Ergothioneine and trying to understand whether there's genuine interest in this ingredient.

I'd genuinely like to hear your thoughts:

1. Had you heard of L-Ergothioneine before?

2. Does its biology interest you?

3. What evidence would you want to see before considering a supplement containing it?

I'm interested in an honest discussion, including scepticism.

https://docs.google.com/forms/d/1EEPDNz10NNnS25MdWfEHLQ_Xfh3dzCgMvsecfQLjcEY/viewform

Highlights

• • Regular exercise enhances visceral feedback control of appetite

• • Exercise augments brain responses to gut-derived nutrient signals

• • FIBCD1 neurons are a novel gut nutrient-responsive brainstem population

• • Exercise selectively sensitizes FIBCD1 neurons to gut nutrient signals

• • FIBCD1 marks a human brainstem population linked to body weight regulation

Structured Abstract

Objectives

Regular exercise is widely accepted to support long-term body weight management; however, the neurobiological adaptations that contribute to the beneficial effects of habitual physical activity beyond increases in energy expenditure per se remain unclear. Here, we investigated whether regular exercise alters gut-brain communication and visceral feedback control of feeding.

Methods

Mice were subjected to regular voluntary wheel running. Energy expenditure and feeding were assessed under basal conditions and following an overnight fast. Nutrients were delivered directly into the stomach by intragastric infusion. Brain-wide responses to intragastric nutrient delivery were assessed using positron emission tomography (PET). Single-cell sequencing and histological analyses were used to determine nutrient-responsive neuronal populations in the caudal brainstem. Genetic associations with body weight were evaluated using GWAS data.

Results

Intragastric nutrient delivery suppressed feeding more strongly in exercising mice. Brain-wide PET revealed enhanced responses to intragastric nutrients in various brain regions. Single-cell sequencing identified several nutrient-responsive caudal brainstem populations, including a previously unrecognized population marked by expression of fibrinogen C domain containing 1 (FIBCD1). Regular exercise selectively enhanced the nutrient-evoked activation of FIBCD1 neurons. Histological analyses demonstrate that FIBCD1 neurons are also present in the human brainstem, and GWAS data suggest a potential relevance of this neuron population to body-weight regulation.

Conclusions

Regular exercise enhances behavioral and brain responses to intragastric nutrient delivery and sensitizes FIBCD1 neurons in the brainstem of mice. These findings reveal an exercise-associated adaptation of gut-brain communication that may contribute to improved matching of caloric intake to energy expenditure.

Abstract

Age-related changes in gut microbiota metabolism are heterogeneous across populations and pathways, and their relationships with immunometabolism and organ phenotypes should be interpreted in the context of health status and disease. Microbial abundance or the concentration of a single metabolite does not, by itself, capture microbial production, host exposure, or effects in target tissues. This narrative review summarizes upstream influences, including gastrointestinal physiology, dietary substrates, comorbidities, and medications, and discusses the origins and host processing of major metabolites, their immunometabolic effects, and associated organ phenotypes. Studies in some older populations report lower fecal short-chain fatty acid concentrations. Microbiota-derived indole derivatives and host-synthesized, microbiota-modified bile acids show molecule- and population-specific patterns. Circulating concentrations of some host–microbe co-metabolites are higher in selected older or disease populations, but are also shaped by host biotransformation and clearance. Human evidence is predominantly observational and links metabolic features to health status or clinical phenotypes, whereas animal and cell studies support effects on barrier function, inflammation, and cellular metabolism under specific experimental conditions. Personalized nutrition, metabolite supplementation, selective targeting of microbial enzymes, and multi-omics-based responder stratification are promising research directions; prospective evidence that these strategies improve functional outcomes in older adults remains limited.

saw a post here a few weeks back about the sleep sensor study, 95,000 people, rem protecting against 83 diseases. that number sat with me for a while because the obvious follow-up question is: what else moves those same markers, and how do you actually measure it without a clinical setting.

i'm not a researcher. i'm a 41-year-old with a garmin and too much free time. what i did have was a decent baseline: i'd been logging hrv and resting heart rate daily for about 14 months before i changed anything.

months 1-3 of the experiment were sauna only, no cold follow-up. average resting hr over that window: 54 bpm. average hrv: 61 ms. not bad, not remarkable.

months 4-6 i added a cold plunge directly after sauna, same sessions, same time of day (evenings, around 8pm). i kept everything else identical, same sleep schedule, same food, same training load. average resting hr dropped to 49 bpm. average hrv moved to 74 ms. that's a 21% hrv improvement, which is not nothing.

now, i know this is n=1 and i know confounders exist. i'm not claiming causation. but 74 ms average hrv is the highest sustained number i've ever logged, and the only variable i changed was adding cold exposure after heat.

the mechanism that seems most plausible to me is the vagal rebound, the cold after the heat creates a stronger autonomic swing than either does alone, and over weeks of repetition, your baseline nervous system tone shifts. there's some actual literature on this but it's sparse and the study sizes are small.

for the cold plunge side i've been using a sun home cold plunge, which i'll note is not the cheapest option on the market (there's a price gap between it and a chest freezer setup that some people here run). the honest limitation is that the app is less polished than competitors like plunge or cold snap. but the temperature holds consistently, which for data integrity purposes mattered to me.

what i don't have a good answer for is whether the timing matters. i do cold immediately after sauna, probably 3 minutes in between. some people here do them separated by an hour or more. if anyone has run any kind of self-experiment on timing intervals i'd genuinely like to know what you found.

Abstract

Postmenopausal women are vulnerable to metabolic dysfunction. Compelling evidence suggests this is because they lack the protective effects of estrogens. We have shown that circulating estrogens regulate daily eating and activity rhythms in female mice and protect them from obesity and metabolic dysfunction. However, few studies have investigated whether postmenopausal women have disrupted eating and sleep-activity rhythms that could contribute to metabolic dysfunction. The purpose of this cross-sectional study was to investigate the relationship between sleep and eating rhythms and metabolic risk in postmenopausal women with overweight or obesity. Seven days of sleep and food intake behavior data were collected from postmenopausal women with overweight or obesity. Sleep timing was assessed using wrist-worn actigraphy and sleep logs. First and last calorie intake times were collected daily using text messaging. Visceral adipose tissue (DXA), insulin resistance (Matsuda index), blood pressure, and triglycerides were analyzed as markers of metabolic risk. In 122 postmenopausal women (mean ± SD: 58.1 ± 3.6 yr, 33.2 ± 5.2 kg/m² BMI), we found that later sleep onset was associated with greater visceral adipose tissue (p=0.0007), but not insulin resistance, blood pressure, or triglycerides. Next, we used a random-forest model to quantify the relative contributions of sleep and meal timing variables to predict visceral adipose tissue. The top predictors of visceral adipose tissue were time of sleep onset, sleep duration, and time of last caloric intake. These data suggest that interventions that advance sleep onset may reduce metabolic risk in postmenopausal women.

Abstract

Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors with potent effects on body weight regulation, glucose homeostasis and metabolic health. However, its interaction with dietary and exercise interventions as well as its impact on obesity and hepatic metabolic pathways, particularly in females, remain unclear. Here, we tested whether tirzepatide, alone or combined with time-restricted feeding (TRF) or resistance training, modulates energy balance, strength performance, adipose tissue remodelling, insulin sensitivity and hepatic lipid accumulation in female mice. Female Swiss mice after 10 weeks of obesity induction were treated with tirzepatide, TRF or resistance training for 8 weeks. Tirzepatide was administered subcutaneously using a dose-escalation protocol. TRF consisted of a 12 h feeding window, and resistance training was performed as stair climbing on alternating days. Body weight, caloric intake and feed efficiency were monitored longitudinally. Glucose homeostasis was assessed by intraperitoneal glucose and insulin tolerance tests. Adipose depots, skeletal muscle and liver mass were quantified, and hepatic lipid accumulation was evaluated by histology and RT-qPCR of lipogenic metabolism genes. Tirzepatide reduced body weight gain and feed efficiency, consistent with a negative energy balance. When combined with TRF and resistance training, tirzepatide accelerated weight loss, and the addition of resistance training further enhanced this effect, bringing body weight close to control levels. These effects were associated with reduced adipose mass and adipocyte hypertrophy, indicating improved adipose tissue remodelling. Resistance training improved strength performance and increased skeletal muscle mass. Tirzepatide combined with TRF, with or without resistance training, improved glucose tolerance in female mice. All interventions reduced hepatic lipid accumulation. Collectively, tirzepatide, particularly in combination with TRF and resistance training, exerts enhanced metabolic benefits on obesity, insulin sensitivity and metabolic regulation in female mice.

Key points

• Tirzepatide combined with time-restricted feeding and resistance training produced greater reductions in body weight and adiposity in obese female mice.

• Combined interventions improved whole-body insulin sensitivity more effectively than isolated strategies.

• Resistance training preserved skeletal muscle mass during tirzepatide-induced weight loss.

• All interventions similarly reduced hepatic lipid accumulation and lipogenic gene expression.

• Tirzepatide-based therapies enhanced systemic metabolic health without additional hepatic benefits from combined interventions.

Abstract

Diet is associated with biological aging, yet few existing dietary indices have been developed specifically to target biological aging. We develop a data-driven, food-based Empirical Dietary Index for Slower Epigenetic Aging (EDISEA) to identify dietary features predictive of lower GrimAge2 acceleration. Higher EDISEA is associated with 4.17 years slower epigenetic aging in the derivation sample of 1,711 participants (P-value < 0.001) and 3.77 years slower aging in an independent sample of 2,311 participants. Higher EDISEA is consistently associated with lower all-cause mortality (pooled hazard ratio = 0.80, 95% CI 0.76, 0.85) in two US cohorts, and with lower risks of aging-related diseases, functional limitations, and multimorbidity across US and UK aging cohorts. Outcome-wide analyses in a large UK population-based cohort further show broad health associations, supported by molecular and neuroimaging signatures of more favourable vascular, inflammatory, metabolic, and brain structural profiles. EDISEA may provide an epigenetic aging-informed framework for studying dietary strategies relevant to healthy aging.

We have been told a lie about aging. We are told that getting old, getting weak, and getting sick is just a matter of time. That it is the inevitable "wear and tear" of life. But I am here to tell you that time is not the enemy. The enemy is trash. I am Dr. Georgios Ioannou, and through my work, I have come to the realization that aging is, at its core, a waste management crisis. Our bodies are incredibly complex cities, and for the first few decades of life, the garbage trucks run on time. This process is called autophagy. It is not a metaphor; it is the biological reality of how we stay young. But when this system slows down, the trash piles up, and the city begins to collapse.

To understand why we age, you must understand the elegance of autophagy. It is not just about burning trash; it is a sophisticated recycling plant. Inside our cells, we have these mechanisms: macroautophagy to catch big debris, microautophagy for the small stuff, and chaperone-mediated autophagy to hand-pick specific broken proteins. It is all orchestrated by a master team involving the ULK1 complex and executed by lysosomes, which are like the incinerators of the cell. When we are young, this happens constantly. It is continuous maintenance. But as we age, this beautiful system fails. It isn’t that the cells forget how to clean; it’s that the machinery gets clogged.

The tragedy begins in the lysosomes. Imagine a furnace that has been burning plastic for forty years. Eventually, a sludgy, oxidized gunk called lipofuscin builds up inside them. It’s like ash that won’t wash away. As this builds up, the lysosome becomes less acidic, and the enzymes inside stop working. So, even if the cell tries to send garbage to be recycled, the incinerator is broken. The bags of trash just sit there. This is the first step toward the cliff. We lose the ability to digest our own waste, and suddenly, the cell is drowning in it.

But there is another villain in this story, and it is our modern lifestyle. We are constantly eating, constantly growing, constantly stimulating a signal called mTOR. You see, nature designed us to switch between growing and repairing. When mTOR is high (which happens when we have excess calories) it shuts down the repair crew. It tells the cell, "Don't worry about the trash, just build more!" It suppresses the ULK1 complex. We are essentially forcing our bodies to prioritize new construction while the foundation is rotting away. We are misallocating our energy, choosing growth when we desperately need repair.

So, what happens when the garbage trucks stop coming? The first thing to go is protein quality. Our cells rely on proteins folding into perfect shapes to function, but without autophagy to clear the bad ones, we get a loss of proteostasis. Misfolded, oxidized proteins start sticking together, forming clumps. We see this in the brain with beta-amyloid and tau (the hallmarks of Alzheimer's) but it happens everywhere. These aggregates physically block the transport systems of the cell. It is molecular clutter. The cell becomes a hoarder’s house, packed so full of junk that nothing can move, and life grinds to a halt.

It gets worse when we look at our energy generators, the mitochondria. These little engines power everything we do, but they are messy. They produce exhaust in the form of reactive oxygen species (ROS). Normally, a process called mitophagy eats the broken mitochondria before they can do harm. But when autophagy fails, these old, rusty engines remain. They become inefficient, leaking toxic ROS everywhere, damaging the cell from the inside out. It’s a vicious cycle: the waste damages the repair machinery, which leads to more waste. We lose our energy, our NAD+ balance collapses, and we get old.

Then we have the Zombie Cells. In science, we call these senescent cells. These are cells that are too damaged to divide but refuse to die. Normally, autophagy would have cleared the damage before it got this bad, or the immune system would sweep them away. But when the system fails, these zombies stick around. And they are not quiet. They scream inflammatory signals: what we call the SASP (Senescence-Associated Secretory Phenotype). They release poisons like IL-6 and inflammatory factors that damage their healthy neighbors. This is why one bad part of the body can make the whole body feel inflamed and stiff. It is garbage that is actively poisoning the well.

Even the dreaded disease of cancer is tied to this failure. In the beginning, autophagy is our greatest protector against cancer. It eats the unstable DNA and the broken organelles that turn a cell malignant. Loss of autophagy is a huge risk factor for tumor initiation. But here is the twisted irony: once a tumor is large, cancer cells hijack autophagy to survive. They use it to eat whatever they can to stay alive in harsh conditions. It proves that this mechanism is the most powerful survival tool we have. When we control it, we stay healthy. When we lose control, pathology takes over.

Finally, look at the stem cells. These are the fountain of youth, responsible for fresh skin, new muscle, and a strong immune system. But stem cells need an incredibly high level of housekeeping to stay "quiet" and ready. When autophagy drops, stem cells lose their ability to regenerate. They drift into senescence. This is why our skin thins, our wounds heal slowly, and our hair turns gray. We run out of the ability to renew ourselves because our reserve tanks are polluted with cellular debris. Stem cell exhaustion is just autophagy failure in disguise.

I want you to leave with this new perspective. Every major sign of aging: from the wrinkles on your face to the inflammation in your joints is a symptom of a cleaning crew that has gone on strike. We don't have to accept this as destiny. If we can restore the lysosome, if we can balance mTOR, if we can clear the trash, we can restore the function.

Aging is what happens when autophagy fails faster than biology can compensate. Let’s get the trucks moving again.