• mert
  • Blog
  • May 3, 2026

Sterile Infammaging

The great thing about getting older is that you always have something to talk about with other old people at a dinner table—your medical problems.  And sterile inflammaging:  chronic, low-grade inflammation without an infectious trigger. It’s one of the constant companions of old age and now considered one of the central drivers of aging. What makes it different from “regular” chronic inflammation is its source. There’s no virus, no bacterial infection, no autoimmune misfire to point at. The inflammation is generated from within—by the body’s own aging cells, tissues, and metabolic byproducts.

Most adults over 65 show measurable elevations in inflammatory markers compared to younger people, and these elevations track closely with frailty, disability, and overall mortality. The phenomenon is so consistent across populations that researchers describe it as a near-universal feature of human aging, distinct from acute or pathogen-driven inflammation.  Besides CRP and ESR, the traditional quick and dirty measures of inflammation, there are some new composite measures that combine multiple inflammatory and biological aging signals:

  • Interleukin-6 (IL-6)
  • TNF-alpha
  • Multi-cytokine panels that capture a broader inflammatory signature than any single marker
  • DNA methylation clocks (epigenetic age) that correlate with inflammatory burden
  • Glycomics, metabolomics, and lipidomics profiles that detect age-related shifts in circulating molecules
  • Immune cell profiling—particularly the ratio of naive to memory T cells, and the accumulation of senescent immune cells like clonal GZMK+ CD8+ T cells, which has emerged as a conserved hallmark of inflammaging

What causes it?

Inflammaging results from several aging processes that all happen to feed inflammation.

  • Cellular senescence. As cells accumulate damage, some stop dividing but refuse to die. These “zombie” cells secrete a cocktail of inflammatory molecules called the senescence-associated secretory phenotype, or SASP—cytokines, chemokines, proteases, and reactive oxygen species. A small population of senescent cells can inflame an entire tissue, and their numbers grow steadily with age.
  • Mitochondrial dysfunction. Aging mitochondria leak more reactive oxygen species and release damaged mitochondrial DNA into the cell. The immune system reads this leaked DNA as a danger signal—essentially mistaking it for bacterial DNA—and mounts an inflammatory response.
  • The immune system itself ages. The thymus shrinks, T cell diversity drops, and T cell lineages shift to inflammatory subtypes.  Innate immunity becomes less precise—quicker to inflame, slower to resolve. Aged immune cells are themselves a major source of inflammatory cytokines.
  • Gut microbiota changes. With age, the gut barrier becomes more permeable and the microbiome shifts toward more pro-inflammatory species. Bacterial fragments leak into circulation and trigger systemic immune activation.
  • Visceral fat—is metabolically active tissue that produces inflammatory signals. The overlap between metabolic disease and inflammaging is so strong that researchers often discuss them together.
  • Defective autophagy. Cells lose the ability to efficiently clear damaged proteins and organelles. The cellular debris itself becomes inflammatory.

These mechanisms reinforce each other. Senescent cells damage mitochondria. Damaged mitochondria activate immune cells. Aging immune cells fail to clear senescent cells.

What are the consequences?

Inflammaging is now linked to most major age-related diseases—not as a side effect, but as a contributor.

  • Cardiovascular disease. Chronic vascular inflammation drives atherosclerosis, endothelial dysfunction, and stiffening of arteries.
  • Neurodegeneration. Inflammatory signaling contributes to Alzheimer’s, Parkinson’s, and age-related cognitive decline. The aging brain shows microglial activation and cytokine elevation that parallels systemic inflammaging.
  • Sarcopenia and frailty. Inflammatory cytokines accelerate muscle protein breakdown and impair regeneration.
  • Type 2 diabetes and metabolic syndrome. Inflammation interferes with insulin signaling and pancreatic function.
  • Cancer. Chronic inflammation creates a tissue environment that favors tumor development and progression.
  • Cerebral small vessel disease. Inflammation damages the blood-brain barrier and the small vessels that supply deep brain structures.
  • Kidney disease. Inflammaging accelerates fibrosis and impairs kidney regeneration.

Looked at this way, many seemingly separate diseases of aging share a common inflammatory undercurrent. This is part of why interventions targeting inflammaging have such broad potential—they don’t treat one disease, they target an upstream driver of many.

How do we prevent and treat it?

Inflammaging is modifiable. While we can’t stop aging, we can reduce the inflammatory burden, and the evidence here keeps growing.

Lifestyle foundations

The interventions with the strongest and most consistent evidence are also the most accessible.

  • Physical activity. Regular exercise lowers IL-6 and CRP, improves immune function, reduces visceral fat, and clears senescent cells from some tissues. Both aerobic and resistance training contribute, and the benefits show up even when exercise begins later in life.
  • Anti-inflammatory diet. Diets emphasizing polyphenol-rich plants, omega-3 fatty acids (from fatty fish, walnuts, flax), olive oil, and minimally processed foods consistently lower inflammatory markers. Mediterranean and traditional Japanese eating patterns are the best-studied examples.
  • Caloric restriction and intermittent fasting. Both reduce inflammatory signaling, improve metabolic health, and trigger autophagy—the cellular cleanup that clears damaged components before they become inflammatory.
  • Sleep.  Inadequate or fragmented sleep elevates inflammatory cytokines within days. Consistent, sufficient sleep is one of the most underrated anti-inflammatory interventions.
  • Stress management. Chronic psychological stress activates inflammatory pathways through HPA axis dysregulation. Meditation, social connection, and stress-reduction practices have measurable effects on inflammatory markers.

Emerging pharmaceutical therapies

Not nearly as effective as lifestyle measures, but worth mentioning.

  • Senolytics are drugs and natural compounds that selectively eliminate senescent cells. The combination of dasatinib and quercetin has shown promise in early human trials. Fisetin, a flavonoid found in strawberries, is also being studied. The idea is simple: clear the zombie cells, and you remove a major source of SASP-driven inflammation.
  • Senomorphics don’t kill senescent cells but suppress their inflammatory output—useful when wholesale removal isn’t feasible.
  • Targeted immunomodulators. IL-11 inhibitors, TLR-modulating compounds, and inflammasome-targeted therapies are in development. Not ready for prime time.
  • Probiotics and prebiotics. Restoring gut microbial balance can reduce systemic inflammatory load, particularly when combined with dietary fiber.
  • Metformin and rapamycin have both shown anti-inflammaging effects in research settings, though their use specifically for healthspan extension remains investigational.
  • NAD+ precursors (such as nicotinamide riboside and NMN) support sirtuin function, which helps regulate inflammatory signaling and mitochondrial health.

Medical treatment of inflammaging has its strongest clinical validation in two landmark trials:

  • CANTOS (2017) — The first major proof of concept. Over 10,000 patients with prior heart attack and elevated CRP received canakinumab (an IL-1β–blocking antibody) or placebo. The drug lowered hsCRP by 26-41% with no effect on cholesterol. The 150 mg dose reduced the primary endpoint (non-fatal MI, stroke, or cardiovascular death) by 15% over 3.7 years. This was a watershed result — it proved that reducing inflammation alone, independent of lipid-lowering, prevents cardiovascular events. Sadly, all-cause mortality didn’t improve because reduced cancer mortality was offset by an increase in fatal infections — a reminder that suppressing immunity has real costs in older people.
  • COLCOT and LoDoCo2 — These trials tested low-dose colchicine (a cheap, generic anti-inflammatory) in heart disease patients. Both showed reductions in atherosclerotic cardiovascular events, but not mortality. In 2023, the FDA approved colchicine 0.5 mg once daily for the secondary prevention of cardiovascular disease — making it the first approved drug specifically for the inflammatory component of heart disease.
  • The STAMINA pilot (published 2025) tested dasatinib + quercetin in 12 older adults with mild cognitive impairment and slow gait. It was small, single-arm, and uncontrolled, but: MoCA cognitive scores improved by 1 point on average and by 2 points significantly in those with the lowest baseline scores; stride length tended to improve; no serious adverse events occurred. This is a tiny study and probably not even worth mentioning until larger randomized trials result.

There are no completed trials yet showing that lowering inflammation extends lifespan or broadly improves healthspan in healthy older adults. The evidence we have is almost entirely from people who already have cardiovascular disease. Whether reducing inflammaging in generally healthy aging adults prevents future disease remains an open question being actively tested.

Inflammaging reframes how we think about aging. It suggests that many of the diseases we accept as inevitable consequences of getting older share a common, addressable upstream driver. The same processes that age your immune system are aging your blood vessels, your brain, your muscles, and your metabolism—all at once.

That’s bad news in the sense that the problem is systemic. But it’s also good news: a single intervention that meaningfully lowers inflammation can ripple across multiple organ systems. Exercise, diet, sleep, stress reduction, and emerging targeted therapies hit a shared mechanism.

Read More
  • mert
  • Blog
  • May 3, 2026

NAD+: The Cofactor at the Center of Aging

Not a week goes by that I don’t get a question or an IG post or some Huberman / Rogansphere related podcast link about supplementing NAD.  Often from the same individual actually.  Is it worth spending your money to take NMN or NR or niacin or any one of the many varieties of this cofactor?

What NAD+ is and actually does

  1. Cellular metabolism:  NAD+ is a coenzyme, meaning it works alongside enzymes rather than acting on its own. It exists in two forms—oxidized (NAD+) and reduced (NADH)—and the cell uses the conversion between them to shuttle electrons. Glycolysis, the citric acid cycle, beta-oxidation of fatty acids: all of them generate ATP only because NAD+ is there to accept electrons and ferry them to the electron transport chain. Without NAD+, mitochondria stop and you don’t make energy.  But most people have enough NAD+.  What is more important is the ratio of NAD+ to NADH.

In a healthy cytoplasm, the free NAD+/NADH ratio is enormous, somewhere on the order of 700:1. In the mitochondrial matrix it is much lower, around 7:1 to 10:1.  If you have lots of NAD+ relative to NADH, oxidativereactions proceed—glucose gets oxidized, fatty acids get burned, electrons flow into the mitochondrial respiratory chain. If you have lots of NADH relative to NAD+, the cell is signaled to stop oxidizing and start storing—fatty acid synthesis, gluconeogenesis from lactate, building rather than breaking down.

Most discussions of metabolic damage focus on oxidative stress—the accumulation of reactive oxygen species. Less appreciated, but possibly equally important in modern disease, is its mirror image: reductive stress, the state of having too much NADH and not enough NAD+.

Chronic overfeeding produces exactly this. When you continuously supply substrate—glucose, fatty acids, amino acids—to a cell that is not actually using much energy, glycolysis and beta-oxidation generate NADH faster than the electron transport chain can dispose of it. The NAD+/NADH ratio collapses. Several things happen as a consequence:  The mitochondria back up. Electron transport slows because complex I cannot offload electrons from NADH fast enough, and the ones that do get loaded tend to leak out as superoxide—the actual source of much of the reactive oxygen species we worry about. Paradoxically, reductive stress causes oxidative stress.

  1. DNA Repair: it is believed by some and not by others that the NAD/NADH ratio affects the function of PARPs which are all DNA repair enzymes.  The PARPs (poly-ADP-ribose polymerases) detect DNA damage and recruit repair machinery. Every time a strand break occurs—and in a typical cell this is thousands of times a day—PARPs consume NAD+ to flag the damage. Less NAD means less DNA repair, which means faster aging.
  2. The sirtuins (SIRT1 through SIRT7) are deacetylases that remove acetyl groups from histones and other proteins. They are central to the cellular response to caloric restriction, they tune mitochondrial biogenesis, and they regulate the expression of stress-response genes. Sirtuins cannot function without NAD+.
  3. Inflammation: CD38, an ectoenzyme present on immune cells and many other tissues, also consumes NAD+. CD38 expression rises substantially with age and with chronic inflammation, and it is now thought to be one of the principal reasons that NAD+ levels fall as we get older.

So NAD+ is being burned through multiple different ways at once—to make energy, to repair DNA, and to fuel an inflammatory enzyme that gets busier with age—while the cell’s capacity to synthesize it appears to decline. Tissue measurements suggest NAD+ levels in skin, muscle, liver, and brain fall by something on the order of 50% between young adulthood and old age. The hypothesis that follows is straightforward: if we can refill the tank, perhaps some of the downstream consequences of low NAD+—mitochondrial dysfunction, impaired DNA repair, chronic inflammation—can be reversed or slowed.

The four oral options

You cannot simply swallow NAD+ and expect it to reach your cells. The molecule is too large and too charged to cross membranes intact; it gets broken down in the gut. So all oral strategies rely on precursors that the body can transport and assemble into NAD+ on the inside.

  1. Niacin (nicotinic acid) is the original B3 vitamin, the one that cures pellagra. It enters the Preiss-Handler pathway and is reliably converted to NAD+ in the liver and elsewhere. It is cheap, well-studied, and has the inconvenient property of producing a vasodilatory flush—the prostaglandin-mediated burning, itching sensation that has caused generations of patients to abandon it.
  2. Niacinamide (nicotinamide, NAM) is the amide form of niacin. It does not cause flushing because it does not act on the same receptor (GPR109A) that mediates the flush. It is converted to NAD+ via the salvage pathway. The catch: at high doses, niacinamide actually inhibits sirtuins. It is a sirtuin product, and product inhibition is exactly what you would expect. So while niacinamide raises NAD+, it may blunt one of the downstream pathways you are trying to activate.
  3. Nicotinamide riboside (NR) is a more recently characterized precursor that bypasses some of the rate-limiting steps in the salvage pathway. Multiple human trials have shown that 300–1000 mg per day of NR reliably raises whole-blood NAD+ levels, is well tolerated, and produces modest improvements in markers like blood pressure and arterial stiffness in older adults.
  4. Nicotinamide mononucleotide (NMN) is one step further down the synthesis pathway than NR. The question of whether NMN itself crosses cell membranes or whether it must first be converted back to NR has been debated for years; the practical answer seems to be that oral NMN does raise NAD+ in humans. A randomized trial in middle-aged adults given 250 mg per day showed elevation of blood NAD+ and prevention of an age-related rise in HOMA-IR (an insulin resistance score) seen in the placebo group. A study in older Japanese men using 250 mg per day for twelve weeks showed improvements in muscle function on certain measures.

The honest summary of the oral precursor literature is this: all of them raise NAD+ in blood, the safety profiles look good across studies running up to a year, and the clinical effects on hard outcomes—cardiovascular events, cognitive decline, mortality—have not yet been demonstrated in adequately powered trials. The studies showing improvements tend to be small, of short duration, and heterogeneous in their endpoints. We are still in the phase where we can say with confidence that these compounds do what they say on the tin biochemically, but not yet that they translate into the kind of healthspan extension that the mouse data suggest is possible.

The IV NAD+ DANGER

A growing cottage industry offers intravenous NAD+ at concierge clinics and longevity spas, often at considerable expense. The pitch is appealing—why mess around with precursors when you can deliver the finished molecule directly?

The instinct that something is off about putting a lot of NAD+ into the bloodstream turns out to be biochemically grounded. Inside the cell, NAD+ is one of the most abundant small molecules in metabolism. Outside the cell, it is something else entirely: a damage-associated molecular pattern, or DAMP. When cells lyse from infection, trauma, or necrosis, they spill their NAD+ into the extracellular space, and the immune system reads this as a signal that something has gone wrong. Extracellular NAD+ triggers inflammatory and immune responses.

This explains the well-known side effect profile of IV NAD+: nausea, malaise, abdominal cramping, sweating, anxiety, chest pressure. These are not idiosyncratic reactions—they are predictable consequences of pushing extracellular NAD+ to supraphysiologic concentrations and activating purinergic signaling. The standard clinical workaround is to infuse very slowly, often over four to six hours, which keeps extracellular concentrations from spiking high enough to trigger the worst of it.

A recent retrospective comparison of IV NAD+ versus IV NR in a real-world clinic setting found that NR could be delivered considerably faster with fewer adverse experiences, and neither produced clinically significant changes in liver enzymes or inflammatory markers at 30 days. This is reassuring as far as it goes, but the studies remain small, short, and uncontrolled. There are no randomized controlled trials demonstrating that IV NAD+ produces clinical benefits beyond what oral precursors provide, and the cost differential is enormous. My own view is that the burden of proof for IV NAD+ is on the people charging $800 a session for it, and that burden has not been met.

The Coronary Drug Project

The most provocative piece of clinical evidence in this entire field comes not from a longevity study but from a 1960s cholesterol trial. The Coronary Drug Project enrolled 8,341 men with prior myocardial infarction and randomized them to placebo or one of several lipid-lowering interventions, including 3 grams per day of niacin. The trial ran from 1966 to 1975. At the end of the active treatment period, niacin showed a modest reduction in nonfatal MI but no significant mortality benefit. A reasonable result. The trial closed.

Then in 1985, nine years after everyone had stopped taking the drug, the investigators did a follow-up to determine vital status on the original cohort. What they found was unexpected enough that it has been discussed ever since. All-cause mortality in the niacin group was 11% lower than in the placebo group (52.0% vs 58.2%, p=0.0004). The benefit was present across every major category of death—coronary, other cardiovascular, cancer, and other. Translated into life expectancy, the niacin recipients had gained roughly 1.6 years of additional life. And remember: they had stopped taking the drug almost a decade earlier.

A late, durable, all-cause mortality benefit from a drug discontinued years before is a strange finding. The conventional explanation has been that niacin’s lipid effects produced a slow accrual of cardiovascular benefit. But the cancer mortality reduction and the cross-category nature of the effect have always sat awkwardly with a pure lipid-lowering story. Looked at through an NAD+ lens, the result is more interpretable: a sustained pharmacologic boost of NAD+ during a critical window may have produced cumulative benefits—better DNA repair capacity, better mitochondrial maintenance, lower CD38-driven inflammation—that compounded over the subsequent decade. This is speculative. It is not what the trial was designed to test. But it is the kind of result that makes you take the pathway seriously.

It is worth noting that subsequent niacin trials in the statin era—AIM-HIGH and HPS2-THRIVE—failed to show cardiovascular benefit when niacin was added on top of statin therapy. Whether this reflects a true loss of benefit in the modern lipid-lowered population, or simply the use of formulations and dosing that did not replicate the original CDP exposure, is debated. The CDP result remains the single most striking long-term outcomes signal in the entire NAD+ literature, and it is over forty years old.

Where this leaves us

Cellular NAD+ falls with age. Restoring it in mice produces effects that look a lot like rejuvenation across multiple tissues. In humans, oral precursors reliably raise cellular NAD+ levels, appear safe over the durations studied, and produce small signals in surrogate markers—blood pressure, arterial stiffness, insulin sensitivity, certain measures of muscle function. They have not yet been shown to extend healthspan or lifespan in adequately powered trials, and such trials are difficult to run at the scale and duration required.

For a patient asking what to do today, my reading is roughly this: the case for some form of B3 supplementation in older adults is reasonable, given the favorable safety profile and the mechanistic plausibility. NR and NMN are the most studied of the modern precursors. Niacin remains the only B3 compound with long-term hard outcomes data, and that data is genuinely impressive even if it is decades old; the flush is the price of admission. High-dose niacinamide is probably best avoided as a longevity strategy given its sirtuin inhibition. IV NAD+ is, in my opinion, at best a way to spend money.  At worst, you are doing physical harm to your body.

For young people who are not depleted in NAD, supplementation seems superfluous.  If the ratio is what matters, what should we expect from oral precursors? They certainly raise the total NAD+ pool. But unless you also do something to keep NADH from accumulating, much of the new NAD+ may simply be reduced to NADH by the substrate the cell is already drowning in. You’ll have a bigger pool, with the same unfavorable distribution.  Concentrate instead on raising the NAD / NADH level through exercise and periodic fasting.

Read More

Advanced Glycation End Products

I have occasionally complained about my mother in law’s bland cooking methods.  Boiled this, steamed that.  How about a sauté?  How about frying something?  And yet, she is aging gracefully and the scientific evidence has begun to justify her insipid cooking.

A growing body of research shows that advanced glycation end products (AGEs) sit at the crossroads of metabolic dysfunction, chronic inflammation, and accelerated aging. They form when sugars bind to proteins or lipids through non‑enzymatic reactions, creating irreversible compounds that accumulate in tissues over time. High‑temperature cooking, processed foods, hyperglycemia, and oxidative stress all accelerate their formation.

How AGEs Form and Why They Accumulate

AGEs arise from the Maillard reaction—initially a browning reaction in foods, but also a slow, ongoing process inside the body. They come from two sources:

  • Exogenous AGEs
    from foods cooked at high temperatures (grilling, frying, roasting) and ultra‑processed products.
  • Endogenous AGEs
    generated in vivo, especially when glucose levels run high or oxidative stress is elevated. Oxford Academic

In humans, endogenous AGE’s predominate.  Exogenous AGEs from food matter too, but their impact is smaller and more modifiable.

Why AGEs Matter for Metabolic Health

AGEs are not passive byproducts; they actively disrupt metabolic homeostasis through several mechanisms:

  1. Chronic Inflammation via RAGE Activation

AGEs bind to the receptor for advanced glycation end products (RAGE), triggering inflammatory signaling cascades. This amplifies oxidative stress and promotes a persistent low‑grade inflammatory state—one of the hallmarks of metabolic syndrome.

  1. Impaired Insulin Sensitivity

By damaging insulin receptors and altering intracellular signaling, AGEs contribute to insulin resistance. High AGE levels are strongly linked to diabetes and its complications.

  1. Structural Damage to Metabolic Tissues

AGEs crosslink collagen and other structural proteins, stiffening blood vessels, impairing microcirculation, and disrupting extracellular matrix integrity. This affects adipose tissue remodeling, pancreatic β‑cell function, and vascular health.

  1. Mitochondrial Stress and Reduced Metabolic Flexibility

Oxidative stress induced by AGEs impairs mitochondrial function, reducing the body’s ability to switch efficiently between fuel sources—an early feature of metabolic decline.

  1. Acceleration of Age‑Related Metabolic Diseases

AGE accumulation is associated with diabetes, cardiovascular disease, kidney dysfunction, and neurodegeneration—conditions that share overlapping metabolic pathways.

The Dietary Connection: How Food Choices Influence AGE Load

Cooking methods dramatically influence AGE content:

  • High‑AGE methods:
    frying, broiling, grilling, roasting
  • Low‑AGE methods:
    steaming, boiling, poaching, slow‑cooking

Processed foods rich in sugars and fats are particularly dense in AGEs. Reducing dietary AGE intake has been shown to improve markers of inflammation and metabolic health.

Strategies to Reduce AGE Burden

Research highlights several interventions that meaningfully lower AGE accumulation:

  • Lower‑temperature cooking
    and moisture‑rich methods
  • Higher intake of antioxidants
    (fruits, vegetables, herbs) to counter oxidative stress
  • Increased dietary fiber
    , which improves glycemic control and reduces endogenous AGE formation
  • Regular physical activity
    , which improves glucose handling and reduces oxidative load
  • Limiting ultra‑processed foods
    and added sugars

Emerging therapies aim to inhibit AGE formation or block RAGE signaling, but lifestyle strategies remain the most accessible and evidence‑supported tools.

Glylo is one evidence based option to reduce the burden of AGE’s that’s commercially available.

The AgeProof Takeaway

AGEs are not just biochemical curiosities—they are active drivers of metabolic dysfunction and accelerators of biological aging. They damage tissues, amplify inflammation, impair insulin signaling, and undermine mitochondrial resilience. The good news: AGE burden is modifiable. Small shifts in cooking methods, food choices, and metabolic health behaviors can meaningfully reduce exposure and slow the metabolic wear‑and‑tear that AGEs impose.

What is the effect size of AGE’s?

Read More

Transposons and Aging

Aging is often described as the slow accumulation of damage—oxidative stress, mitochondrial decline, epigenetic drift. But one of the most intriguing and increasingly central players in this process isn’t a metabolic byproduct or a failing repair system. It’s a piece of DNA that behaves like it still remembers being a virus.

These sequences are called transposable elements, or transposons. They make up nearly half of the human genome and are probably related to ancient retroviruses that have been fossilized into our DNA. For most of our lives, they sit quietly, locked down by epigenetic machinery. But with age, that lockdown weakens. And when transposons wake up, they cause trouble.  They trigger the manufacture of alien products and induce inflammation.

Understanding how and why this happens is opening a new frontier in longevity science.

What Exactly Are Transposons?

Transposons are DNA sequences that can copy and paste themselves into new locations in the genome.  They are present in all DNA based life forms and were originally described as “jumping genes” in corn plants, where transposons can make up the majority of genetic information.

As sequences of DNA, they hijack the cell’s own protein machinery, directing it to insert new copies of the transposon into fresh genomic territory. Sometimes these insertions land harmlessly. Other times they disrupt essential genes or regulatory regions.

Where did these sequences come from?

As mentioned above, the leading theory is that they are the fossilized remains of ancient viral infections.  Another theory is that they predate viruses and represent some genetic information that evolved because jumping genes confer a survival advantage–in addition to causing havoc, transposons have also been powerful engines of evolution, reshaping gene networks and creating new regulatory elements.  Indeed some organisms with an abundance of transposable elements do not experience reduced lifespans, so the narrative that they are necessarily harmful may be an oversimplification.

How the Body Keeps Transposons Contained

In early life, transposons are tightly suppressed. The genome is packaged so that transposon‑rich regions are buried in heterochromatin, a dense, inaccessible form of DNA. Epigenetic marks—methylation, histone modifications—reinforce this lockdown.  The result is a genome that is orderly, quiet, and stable. But epigenetic regulation declines with age and loss of tissue identity. As chromatin structure loosens and methylation patterns erode, the once‑silent transposons begin to stir.

Aging and the Awakening 

With advancing age, several things happen simultaneously:

  • Heterochromatin becomes patchy and disorganized
  • DNA methylation patterns erode
  • Histone modifications shift toward a more open chromatin state
  • Transposon‑silencing proteins decline in abundance and fidelity

This combination creates the perfect storm.  Transposons that were once locked away become transcriptionally active. They begin producing RNA and, in some cases, proteins capable of reinserting themselves into new genomic locations.

The Damage Isn’t Just Mutational—It’s Immunological

Transposon activity carries the risk of mutating important genes, and that does happen. But the more immediate and systemic threat is inflammation.

When transposons activate, they generate RNA and DNA fragments that look suspiciously like viral material. The cell’s innate immune system recognizes these molecules as foreign and launches an antiviral response.

This leads to:

  • Chronic interferon signaling
  • Activation of cytosolic DNA sensors
  • Inflammatory cascades that spread beyond the cell of origin (inflammaging)

In other words, the body reacts to its own genome as if it were under viral attack.

This contributes to the persistent, low‑grade, sterile inflammation—inflammaging—that disrupts tissue function across the body.

Some researchers now argue that this inflammatory signaling, not the mutational damage, is the primary way transposons accelerate aging.

The Epigenetic–Transposon Feedback Loop

One of the most striking features of transposon biology is how tightly it is intertwined with epigenetic aging.

  • Epigenetic drift → transposon activation
  • Transposon activation → inflammatory signaling
  • Inflammation → further epigenetic disruption

This creates a self‑reinforcing loop that pushes cells toward dysfunction, senescence, and immune activation. It’s a genomic version of a feedback amplifier: once the system destabilizes, the noise grows louder.

This loop may help explain why interventions that restore youthful chromatin structure—such as partial reprogramming—also suppress transposon activity.

Transposons sit at the intersection of several hallmarks of aging:

  • Genomic instability
  • Epigenetic alterations
  • Loss of proteostasis
  • Deregulated nutrient sensing
  • Chronic inflammation

They are active participants in the aging process and this makes them an appealing target for intervention. Strategies under investigation include:

  • Reinforcing heterochromatin structure (reprogramming)
  • Enhancing transposon‑silencing pathways
  • Dampening transposon‑triggered inflammatory signaling
  • Blocking reverse transcriptase activity

Reverse transcriptase inhibition is a plausible geroscience target.  Experiments on fruit flies have shown positive effects of treatment with the RT inhibitor lamivudine–increase in longevity and stress tolerance. But no randomized human trials have tested RT inhibitors as longevity or healthspan interventions.  RT inhibitors have well‑characterized toxicities (mitochondrial, metabolic, hepatic, bone), which are non‑trivial for long‑term use in otherwise healthy people.  That hasn’t stopped people from trying: in one phase 2 trial, patients with Alzheimer’s who were given RT inhibitors showed some improvement. 

Read More

Why do we have to die?

If we are to understand aging, the primary question is why should there be aging and death in the first place?  Why is it almost universal in living organisms and what evolutionary purpose, if any, might aging and death serve?  First let’s clarify that I don’t have any formal education in evolutionary biology, I think it’s a fascinating field and I’m frustrated by my status as a dilettante.  Yet I proceed in the spirit of an amateur and offer my hypothesis.

Aging really looks programmed. Take the Pacific salmon—he swims upstream, spawns, and dies on a reliable schedule. Humans lose muscle, go through menopause, develop male-pattern baldness, and accumulate frailty in stereotyped sequence. The epigenetic clocks developed by Horvath and others tick along a remarkably consistent trajectory across individuals—the methylation pattern of a sixty-year-old liver looks reliably different from that of a thirty-year-old liver, in ways that are not random.

If aging were simply the accumulation of damage, we would expect it to look noisy and idiosyncratic. Instead it looks more like development.  It looks like puberty: a sequence of events unfolding on a clock. Are there bald adolescents?  Not so much.  The question is whether this appearance of programming reflects something real, or whether it is an illusion produced by deeper, non-programmatic forces.

Yet the mainstream view of aging is hostile to a program.  Aging, in the conventional perspective, is a manifestation of neglect rather than intent.

Mutation accumulation (Medawar, 1952) holds that harmful mutations expressed late in life are weakly selected against, because most organisms in the wild are killed by predators, disease, or accidents long before those mutations matter. Over many generations, late-acting harmful mutations become part of the genome simply because they cannot get selected against prior to reproduction. This explains some features of aging—particularly the late-life rise in conditions caused by recessive variants—but it does not predict the choreographed quality of the aging process.

Antagonistic pleiotropy (Williams, 1957) goes further. It proposes that some genes are actively selected for despite causing aging, because the same genes confer reproductive advantages early in life.  Hyperfunction that primes an organism for reproduction ultimately speeds aging, burning the organism out.  Williams’s framework can explain a great deal of what looks programmed about aging, because under antagonistic pleiotropy, a great deal of aging really is the predictable downstream consequence of genes that have been actively selected for.

Disposable soma (Kirkwood, 1977) extends this argument: the cell must allocate finite resources between reproduction and somatic maintenance. An organism that spent everything on DNA repair would be outcompeted by one that spent more on offspring. Aging emerges as the consequence of an evolved allocation strategy.

These three theories are usually presented as a package, but they are distinct and partly opposed, and together they explain much of what we observe. I want to concede this clearly: most of what looks programmatic about aging is probably accounted for by these mechanisms, particularly antagonistic pleiotropy. Anyone proposing something stronger needs to explain what AP cannot.

Three features of aging give me pause about whether antagonistic pleiotropy is the whole story.

  1. The precision of the program. The epigenetic clocks tick at a consistent rate across individuals of the same species, and at very different rates across species. A mouse and a human have nearly identical genomes at the level of base pairs that matter for cellular machinery, yet the mouse ages thirty times faster. The difference is regulatory and developmental, and it looks tuned. Antagonistic pleiotropy can produce aging, but it is not obvious why it would produce aging on a clock.
  2. Continuity with development. The molecular machinery that drives development—Hox genes, hormonal cascades, the epigenetic regulatory apparatus—does not switch off at sexual maturity but rather it keeps running. The same systems that orchestrate puberty may also orchestrate menopause, sarcopenia, and immunosenescence. If aging were just the accumulated cost of pleiotropic genes optimized for early reproduction, we would not necessarily expect it to look like a continuation of the developmental program. Yet it does.
  3. Sequence and uniformity. Within a species, the order in which things fail is conserved. Hair grays before joints fail before cognition declines. This is not what stochastic damage produces.  The sequential conserved nature of aging makes it feel like programatic development, and the mechanism for the program is likely epigenetic.

Now suppose that, on top of antagonistic pleiotropy, there is some additional selection pressure favoring finite lifespans because populations of finite-lived organisms adapt faster than populations of long-lived ones. More generational turnover means more iterations of natural selection per unit time, which means faster accumulation of beneficial variants, which means a better chance of tracking environmental change.

In environments where change is rapid, such as the Cambrian explosion and the post-permian recovery, the early Cenozoic period and most recently, the Pleistocene epoch, there is accelerated evolutionary change.  This is shown in the fossil record.  Rapid evolution is advantageous during these periods of instability because organisms with accelerated evolutionary change will be better able to specialize to new niches and outcompete and displace those who evolve slowly.  A population that adapts twice as fast can outcompete and displace a population that adapts half as fast, even if the latter has more reproductive years per individual.

But then there is the problem of the cheater.  Imagine a population of programmed-death organisms. A single mutant arises whose program fails and it becomes the immortal cheater. In the very next generation, the cheater reproduces while the rest of the population dies on schedule. The cheater’s offspring inherit the broken program. Within a few generations, the cheater lineage dominates. But what I’m saying is that this would need to be balanced against the evolutionary fitness accrued by shorter lifespans. In other words, whatever evolutionary benefit of more offspring accrued from a longer cheating life would be balanced by better evolutionary fitness from more cycles of natural selection due to shorter life.  So the cheater genotype ultimately loses out to the short-lived genotype.

This is the end of my brief career as an evolutionary biologist.

Read More

Circadian interventions

We have internal rhythms that align with the rotation of the planet.  Most famously, there is the rhythmic secretion of melatonin at night and a spike of cortisol in the morning.  These and myriad other oscillations are controlled by aptly named clock genes that are present in every cell of the body. Clock genes work together to maintain and synchronize the timing of various physiological and behavioral processes in the human body. Some of the key clock genes are CLOCK, BMAL1, PER, and CRY.   The molecular clock in individual cells is synchronized by a master oscillator located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN receives light signals from the retina, which helps to align the internal clock with the external light-dark cycle, ensuring that the circadian rhythm is properly entrained to the external environment.  Circadian dysfunction that occurs when peripheral clocks are out of sync with the central clock, as during jet lag or shift work, can lead to metabolic dysfunction. The function of the clock genes and the mechanisms of circadian rhythmicity have been elucidated to fascinating detail–though their translation to clinical medicine has not happened.  But according to this Montenegrin paper, circadian timing can be easily applied for interventions related to metabolic health.

Certainly the most obvious and best studied of the circadian recommendations is to align sleep with the day and night cycles.  Following that, eating while the sun is out is a good rule of thumb, we know that eating outside a circadian window affects how we use our calories and increases the likelihood of metabolic dysfunction.  Like many who practice obesity medicine, I suggest front loading calories earlier in the day.

Exercise in the morning–I’ve read different perspectives, but the paper makes a good case for timing exercise early.  They point out that melatonin phase delays are associated with exercise in the evening or overnight.

Antihypertensives:  ACE inhibitors and ARB’s should be taken in the evening–I didn’t know this. Blood pressure follows a diurnal rhythm—typically dipping at night. Administering certain antihypertensives (like ACE inhibitors or ARBs) in the evening can restore nocturnal dipping and reduce early morning cardiovascular events, which are more common due to cortisol surges and sympathetic activation

Statins:  Should also be taken at night.  Good to know.  Put it on your nightstand. Cholesterol synthesis peaks at night, especially in individuals on low-fat diets. Short-acting statins like simvastatin are more effective when taken in the evening, whereas longer-acting ones (e.g., atorvastatin) are less time-sensitive.

Metformin:  take it at night

Steroids: Endogenous cortisol peaks in the early morning. Administering exogenous corticosteroids like prednisone in the early morning mimics this rhythm and minimizes HPA axis suppression and insomnia.

Breakfast:  Is it the most important meal of the day or should you skip breakfast to prolong your fast?  It appears that calories eaten for breakfast are less fattening, account for more energy expenditure and may reinforce important clock genes.  Which is to say, eat your breakfast.

GLP-1 RA’s in the afternoon to sync with endogenous GLP-1 secretion–probably less relevant since people take once weekly dosing.

Read More

Why Nature Wants Us to be Fat by Richard Johnson

The two popular theories that purport to explain the obesity pandemic are the carbohydrate insulin model and the standard model of energy balance.  In Why Nature Wants Us to be Fat, nephrologist Richard Johnson bravely proposes another theory:  the survival switch.

In his formulation, nature has evolved a survival mechanism allowing organisms to rapidly gain weight in response to stress or in preparation for periods of scarcity.  It is meant to be turned on occasionally in response to adversity, but our food environment has interacted with our evolutionary biology to turn the switch on continuously, leading to widespread obesity.  The survival switch is mediated by the molecule fructose, and Johnson pins much of the blame on pervasive consumption of high fructose containing foods and beverages which were introduced in the 1970’s.  Fructose metabolism triggers an intracellular starvation type response in the liver that ultimately leads to leptin resistance and diminished satiety, which then causes persistently disordered appetite.  Fructose causes obesity not because of its caloric or nutritive value, but rather by hijacking appetite.  Sucrose too is implicated, as it is broken down to equal parts fructose and glucose.

The book impressively draws from biochemistry and clinical science as well as comparative biology, evolutionary science, bio-anthropology and paleontology to synthesize a coherent theory to explain our current global metabolic perdicament.  According to Johnson, a classic example of the survival switch is mammalian hibernation.  To take that example, in preparation for winter the bear markedly ramps up its consumption of fructose-containing blueberries in order to build fat stores, which become a source of both calories and water during its hibernation.  Similarly, birds often switch from insect diets to fruit and nectar-filled diets as winter approaches in order to gain fat.  In this way animal and fruit-bearing plant life are in seasonal harmony.

The fundamental issue is that fructose metabolism simulates an intracellular energy deficit in a dose dependent fashion by rapidly diminishing intracellular ATP by 20-60%.  As a result, appetite and fat deposition are stimulated.  Fructose is known to cause central leptin resistance by hypothalamic inflammation, which would naturally increase appetite.  Additionally, in the presence of fructose, saturated fats are particularly obesogenic.  Finally, mitochondria suffer oxidative stress because of fructose.

In the absence of fructose, other stimuli such as high salt, dehydration and umami (glutamate) can also trigger the survival switch by pushing conversion of glucose to sorbitol and then to fructose through the polyol pathway. High glycemic carbs will  increase fructose production as well, and this is probably the number one way in which people are exposed to fructose today outside of supplemented HFCS.

According to Johnson, animals are drawn to salt-licks because the salt triggers the conversion of glucose to fructose, which in turn helps them put on weight. To the extent that ultra-processed foods are formulated with high concentrations of salt and sugar, they are continually triggering this metabolic switch on a global scale.

Johnson suggests inhibitors of fructose metabolism would prevent the adverse consequences of the western diet and would by themselves prevent NAFLD.  There happens to be a number of Pharma groups working on fructokinase inhibitors.  Luteolin is a naturally occurring flavone that blocks fructose metabolism and has been associated with renal protection.

This is a fascinating book by a researcher who has stature and standing in the field, but his identification of the survival switch as the cause of the majority of  maladies afflicting mankind gives pause.    Yet the theory is cohesive, supported by empirical evidence and powerfully explains much of our current predicament.  I am swayed.

Read More

Muscle, Protein and Aging

Muscle is a metabolically active tissue that plays a central role in health and longevity.  Beyond functional roles such as helping one get up from a chair, going up stairs and avoiding falls as we age, muscle accounts for 75% of glucose disposal and makes the greatest contribution to resting energy expenditure of any tissue in the body.  For these reasons, we need to be mindful of preserving our muscle mass if we are to age well.  Unfortunately, it becomes harder to maintain (let alone build) muscle as we get older.  There is evidence of anabolic resistance in the elderly, a barrier to building muscle, and it is not uncommon for the elderly become sarcopenic.  Sarcopenia (from the Greek “loss of flesh”) can be a tremendous burden on geriatric populations and is the leading cause of frailty and deterioration.  What follows is a discussion of muscle metabolism that owes a debt of gratitude to the food industry scientist Don Layman and also to a review article by Tezze et. al.

Protein
The main drivers of muscle synthesis and retention are resistance exercise and to a lesser extent, protein intake.   But what kind of exercise?  And what kind of protein?  And how much?  And when?

Not all protein is equal.  

  • Protein is made of amino acids, some of which are categorized as essential because they cannot be manufactured by our body and must be consumed.
  • The essential amino acids are: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
    • Leucine in particular is thought to be a notable driver of muscle protein synthesis
    • Leucine is also a primary driver of the enzyme mtorc1, which is thought to advance the ticking of the clock (aging).
  • Proteins differ in their amino acid composition and degree of binding / accessibility.
  • All essential amino acids are derived from bacteria.
    • Plants will absorb them as part of their root system to incorporate into plant protein.
    • Ruminative animals like cows have nitrogen fixing bacteria in their stomachs that very efficiently convert plant protein in grass / grain to essential amino acids, accounting for the high protein of herbivores who themselves consume very little protein.
  • Typically, meats and fish have a complete assortment of essential amino acids that are easily accessible for use in the body.
  • Plants are often deficient in various essential amino acids and plant protein is more likely to present difficulties with extraction. They have a lower protein digestibility corrected amino acid score.
      • DIAAS is the digestible indispensable amino acid score.
      • To take an example, whey protein, a byproduct of cheesemaking, is 20% better than a soy protein isolate on the basis of its essential amino acids
  • This doesn’t mean that plant protein is not good for you.  Scientists like Walter Longo suggest that low protein / plant based diets throughout life may limit inflammation and slow the ticking of the clock.
  • The case of frailty / sarcopenia is a separate issue considered below.

Muscle Homeostasis

  • Muscle tissue is in a constant state of turnover characterized by rates of muscle protein breakdown and muscle protein synthesis.
  • The relationship of building muscle tissue to fostering longevity is seemingly paradoxical.  On the one hand, having muscle mass is good for aging and associated with less frailty.  On the other hand, it requires the anabolic activation of mtorc1, which is a driver of aging and frailty.  How do we reconcile these realities?
    • Muscle protein breakdown is inhibited by insulin, which is the body’s main anabolic hormone.
    • Beyond that, muscle protein synthesis is more heavily regulated and amenable to modification, typically stimulated by agents that increase the activity of mtor, which is believed to accelerate aging. We know that branched chain amino acids such as leucine drive mTORC1 and drive muscle growth.
    • Yet ITP studies in mice suggest L-leucine enriched diets reduce lifespan (ITP 2017) and chronic activation of mTORC1 stimulates progressive muscle damage and loss. Moreover, inhibition of mTORC1 with rapamycin prevents age-related muscle loss (1).
  • The resolution of this paradox is lies in the complexity of muscle homeostasis and the mTORC1 enzyme and there are various explanations.  Some authors (1) have suggested that Akt dependent activation of mTORC1 prevents muscle atrophy whereas Akt independent pathways will induce muscle atrophy, largely mediated by mitochondrial oxidative stress.  Others (2) have suggested that mTORC1 inhibition rejuvenates muscle stem cells by preventing senescence.

Another way of looking at this issue is to consider the essential amino acid leucine, which is a relatively muscle-specific activator of mtor.  Insulin on the other hand activates mtor in a range of tissues.  What this means functionally is that people who eat a lot of small carbohydrate meals, each of which leads to the secretion of insulin, continuously activate mTOR and drive anabolic pathways / aging across tissues.  This is probably the worst-case scenario and a real justification not to snack.   On the other hand, infrequent / periodic high protein meals with large leucine loads will stimulate muscle growth while reducing broader mtor activation associated with snacking.  Does this mean there is no role for carbs in the diet?  Of course, not, but that is a matter for another time.

Timing of protein consumption—is it better to spread your intake across the day or consume the bulk of your protein in one or two meal?

  • To build muscle you need large individual servings of protein.  Muscle anabolism is not stimulated until you have a significant ingestion. Muscle tissue senses the concentration of amino acids in the blood that serve as a signal that a meal has adequate quality for muscle to trigger the very expensive process of protein synthesis.
  • Protein should be front loaded in the day, ~30g for breakfast to interrupt overnight catabolism and then at dinner to forestall overnight catabolism. Ideally, we pair this with some resistance activity.
  • For the rest of your physiological needs (cardiac, liver, etc.), you don’t need large individual servings.
  • This is not true for kids—their muscle growth is more insulin oriented. They can use protein regardless of the absorption schedule.

Exercise and muscle

  • Resistance exercise is a necessary co-factor for muscle growth along with protein.
    • Resistance exercise stresses the muscle, disrupting homeostasis and leading to protein turnover. With protein turnover, there is protein misfolding, leading to endoplasmic reticulum stress.
    • ER stress leads to the activation of the “integrated stress response” a signaling pathway whose goal is to restore muscle homeostasis.
    • How? via upregulation of ATF4, which controls LARS, a leucine sensor.  Clearly more complicated than this, but here’s your broad outline.
  • Exercise induces both hyperplasia and hypertrophy of muscle fibers. In other words, it increases both the number of fibers and their size.
  • Exercise enhances the ability of the muscle to take-up more amino acids from the bloodstream, and this effect lasts multiple days.

Protein as a diet food

  • Protein is also the most satiating food.
  • It also has a higher thermogenic effect (burns more calories) than either carbs or fat. So eating protein it increases energy consumption.
  • Hi protein percentages during dieting preserves muscle mass.

Protein use / reversing catabolism with age

  • As we get older, our ability to use protein is diminished, referred to as “anabolic inflexibility.”
  • This is partly due to diminished physical activity with age, but also because of features intrinsic to the muscle tissue.
  • This anabolic resistance can be largely overcome by increasing protein intake.  Yet you also need resistance–it doesn’t matter how much protein you consume if you don’t also engage in some degree of muscle exercise. You need both.
  • Older adults need more protein.  There are varying recommendations between, 1-1.5 mg/kg/day (3), keeping in mind that not all protein is created equal.
  • Plant or animal protein?  In one recent prospective cohort study from Hong Kong, older patients who ate plant protein were less likely to develop sarcopenia than those who ate animal protein whereas those who ate predominantly animal protein were more effectively rescued from sarcopenia.
  • Beyond driving muscle synthesis, certain branched chain amino acids found in animal sources such as isoleucine and isoleucine may actually drive mtor and accelerate aging.  In which case, in the setting of tonically activated mtor (middle/old age), a diet high in protein from vegetable sources makes most sense.
  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738401/?fbclid=IwAR3vAqW1MLIF-kY1utROauhs2i8xHFSlqjeL95SRN02Cdgoif-FW1PWXw0c
  2. https://www.mikhailblagosklonny.com/blog/how-rapamycin-prevents-muscle-loss-and-sarcopenia-first-draft/
  3. https://pubmed.ncbi.nlm.nih.gov/24039411/
Read More

Metabolic Syndrome

The diagram below details how overfeeding will lead to the so-called metabolic syndrome, a cluster of conditions that are linked and can lead to vascular disease, stroke and heart attacks.  The components of  metabolic syndrome are hypertriglyceridemia, truncal obesity, hypertension, diabetes and low HDL.  This diagram is a simplification, it elaborates an insulin-centric model, and it’s important to recognize that there are other models.

The overfed state means the cells of the body–primarily muscle, which accounts for 80% of the body’s glucose disposal, and adipose tissue–have been overwhelmed with fuel and become overstuffed.  Insulin is an important player in this schema because glucose transport into muscles requires insulin to get nutrition into the cell.  When the cells are full, they reduce their expression of insulin-dependent glut4 transporters, making it harder to push glucose into the cell.  This resistance can be overcome by manufacturing more insulin, which is how to body initially responds to the problem of rising glucose concentrations in the extra-cellular space.  Imagine insulin to be the hose pressure pushing gas into the tank.  The more stuffed the cells are, the more insulin you need to drive nutrition intracellularly, and this is precisely the phenotype of insulin resistance.  The pancreas is the hose pump in this analogy, and with prolonged pressure, it can fail leading to diabetes.  

Meanwhile glucose that should be going into the muscles and fat cells overflows from that compartment and is instead taken up by the liver in an insulin-independent process.  In the liver, glucose is converted to saturated fat through de novo lipogenesis, ultimately leading to non-alcoholic fatty liver disease (NAFLD), which can progress to cirrhosis and ultimately liver failure.  NAFLD has become the leading reason for referral to liver transplant centers.  

Meanwhile, the very high circulating levels of insulin cause sodium retention in the kidney, creating salt-sensitive hypertension.  At the same time, insulin acts more broadly as a growth factor in the body, and high levels of circulating insulin are associated with accelerated cell division and carcinogenesis.  

This schema is the backstory of the American healthcare system.  An ever rising percentage of patients in any emergency department have hypertension, hyperlipidemia, truncal obesity and diabetes.

Read More

Metabolic Flexibility

Humans evolved in the setting of periodic food scarcity during which we developed the ability to rapidly switch between different fuel sources.  We are designed by evolution to burn fat in our fasting state and to burn primarily carbohydrates in our fed state in order to generate energy in the form of ATP.  All of this occurs in our mitochondria.  But with the development of the modern industrial food environment and ready access to overnutrition combined with less energy expenditure compared to the conditions under which we evolved, we find ourselves overnourished and at odds with our evolutionary design.  One consequence of this mismatch is impaired fuel switching in the mitochondria—we lose the ability to easily switch between lipids and glucose that marks a healthy metabolism.  As a result, our engines are inefficient, we have trouble burning fat while fasting, we are hungrier sooner after a meal, we eat more and find ourselves in a feed forward loop.  Eventually we develop obesity and the diseases related to insulin resistance such as diabetes, metabolic syndrome, NAFLD and ultimately cancer.   At least these are the claims.  What follows is an abstract of a good review paper published earlier this week that examines the concept of metabolic flexibility.

How and why does metabolic inflexibility occur?  

With chronic overnutrition (aka the Standard American Diet), cells become overstuffed and congested with macronutrients, overwhelming the enzymatic mechanisms of metabolism and leading to accumulation of incompletely oxidized substrates–the details of this process are probably not as interesting for our purposes as are the consequences.  These substrates harm mitochondria through oxidative stress from free radical damage and acetylation / protein modification due to acetyl coA accumulation.  The damage actually reduces the number of mitochondria as well as changing their functional morphology–the mitochondria look different and their performance is degraded.   The plasticity of the fuel switch deteriorates, leading to a sluggish metabolic response to nutritional cues.  Imagine a hybrid vehicle whose gas motor is flooded and so it can only use electricity.  And maybe the gas tank is expansile and is ever filling.  (I wish I could think of a better metaphor but I’m a poor mechanic).

At the same time, the overfed state also requires increasing amounts of insulin to push glucose into cells via insulin dependent glut4 transporters.  Imagine insulin to be the hose pressure pushing gas into the tank.  The more stuffed the cells are, the more insulin you need to drive nutrition intracellularly, and this is precisely the phenotype of insulin resistance.  The pancreas is the hose pump in this analogy, and with prolonged pressure, it can fail leading to diabetes.  Meanwhile glucose that should be going into the muscles and fat cells is instead taken up by the liver in an insulin independent process and converted to fat through de novo lipogenesis, ultimately leading to NAFLD–now the leading cause of liver failure.  The very high circulating levels of insulin cause sodium retention in the kidney, creating the phenotype of salt-sensitive hypertension.  Insulin is also a growth factor, and high levels are associated with carcinogenesis.  This is the backstory of the American healthcare system.

Insulin resistance and metabolic inflexibility are intertwined and it’s not clear which comes first, but they relate to each other and are both a consequence of overfeeding.  One reason this topic is of clinical interest is that people with metabolic inflexibility have problems burning fat in the fasting state.  They get hungry sooner and have trouble with fasting.   The intracellular availability of glucose determines the nature of substrate oxidation in human subjects (1).  If there is an excess of glucose, the cell will preferentially oxidize the glucose.  Otherwise it will turn to fat.

How do we treat this metabolic rigidity?

  1. Diminish the nutrition going into the cell
    1. Caloric restriction: since the problem begins with too much energy, an energy deficit, regardless of macronutrient balance, is a reasonable first step toward relieving substrate competition.  I don’t think you need to go low carb or keto, though some people may find it easier to do so in order to manage their hunger.  Calorie restriction permits cells to decongest themselves of unused substrate and restore normal membrane potential across mitochondria.  Losing weight is the best and perhaps only valid treatment for fatty liver and can reverse insulin resistance and DM2 in its early stages.  So eating less is how to repair the metabolic inflexibility which derives from eating too much–it feels like an astute observation of the obvious, but there may be a special way of eating less that is especially effective.  Fasting.
    2. Fasting: starvation has benefits beyond calorie restriction alone.  We evolved to cope with periods of starvation and the metabolic program triggered by fasting has diverse benefits beginning with exhaustion of liver glycogen stores and initiation of ketosis. Burning ketones is metabolically healthy for a number of reasons, particularly as we age.  At the cellular level, fasting induces autophagy to remove damaged proteins, mitochondrial biogenesis and mitophagy.  The issue of fasting is, of course, a larger one and care must be taken to preserve lean muscle mass, but the rationale to starting a diet with a fast is that lipid oxidation is kickstarted by more rapidly inducing metabolic flexibility.
    3. SGLT2 inhibitors:  SGLT2 (sodium glucose cotransporter-2) inhibitors force the kidneys to spill glucose in the urine leading to a condition that mimics caloric restriction.  These drugs have been shown to be kidney protective, to reduce weight, to reduce blood pressure and to improve outcomes in congestive heart failure.  It turns out that they also promote beiging of adipocytes (in mice)—the brown fat that generates heat and burns calories in the process.  Unclear if this is relevant in humans.  At the mitochondrial level, SGLT2i’s permit the cell to decongest itself of the metabolic substrates that have caused all the damage.  Taking SGLT2i at night, according to the authors, amplifies the effects of an overnight fast.
  1. Improve factors that mitigate mitochondrial stress
    1. Restoration of glutathione with glyNAC to counter oxidant stress
    2. Carnitine based acetyl-group buffering: theoretical. I don’t see any evidence that carnitine supplementation is of value at this point.
  1. Increase energy expenditure
    1. Aerobic exercise, particularly zone 2 exercise is the best way to improve the number of mitochondria and their function. There is a strong association described between exercise and metabolic flexibility.  Even after one episode of exercise, insulin resistance and mitochondrial function improve.
    2. Resistance training: bigger muscles means a bigger glucose sink, a greater buffer to accommodate nutrient load in the fed state.

 

 

Footnote

(1) https://journals.physiology.org/doi/abs/10.1152/ajpendo.1996.270.4.e733

Read More