Frequently Asked Questions

If you flip through the page corners from back to front, you'll see a flip-book-style cartoon illustrating the chain reaction of lipid peroxidation, with grey penguins representing D-PUFAs. Additional guidance on page 69 and page 265. This animation only works in the printed edition.

Aside from adopting the core approach discussed in this book (which would amount to adding a new habit rather than breaking an old one), the single most impactful habit to drop is the use of "vegetable" oils — both directly and in foods that contain them, such as mayonnaise and most processed products. Eliminating these oils entirely is a strong step toward stopping LPO, reducing oxidative stress and inflammaging, and slowing age-related damage.

We can't stop aging outright, but we can slow it down — potentially long enough for each new generation of therapies to extend our healthy years even further. This idea, often called "longevity escape velocity" by Aubrey de Grey, suggests that if medical advances keep arriving fast enough, each one buys us time to reach the next, hopefully, ad infinitum.

No — but it is the moment to act. Recent research suggests that aging doesn't progress in a straight line; instead, it accelerates around ages 34–36, 40–44, and 60–64. Starting at 34 or 40 would have been ideal, but if those windows have passed, your early 60s are a critical point to make meaningful changes.

As skin is the interface separating us from the world, maintaining healthy-looking skin is key to that goal. There is plenty of PUFAs in the skin, so preventing their peroxidation is a smart way to limit inflammation, malodor and lipofuscin formation. D-PUFAs may help reduce LPO in the skin, but so will minimizing the sun exposure. If you choose to get tattoos, avoid excessive sunlight on them, and try to use inks free of transition metals. For more detail, see section 4.7. "Skin in the Game" in the book.

The aging process is not uniform. Based on blood markers, Tony Wyss-Coray identifies four age clusters: up to 34, 34–60, 61–78, and above 78 years. According to Michael Snyder, RNA, lipid, and metabolite analyses point to two "breakpoints," around ages 40–45 and 60. We're all familiar with the expected changes that come with these transitions — menopause, slower metabolism of alcohol and coffee, declining immune function and creeping inflammaging...

Are these timepoints related to the whole organism, or could they be caused by a weakest link such as the fastest-aging organs, or even changes at the cellular or subcellular level? Several organ-specific "ageotypes" have been identified. Initially limited to (1)-(4), the current list includes nine: (1) kidney, (2) liver, (3) immune system, (4) metabolic aging, (5) cardiovascular system, (6) physical fitness/muscle, (7) sex hormones, (8) facial skin, and (9) gut microbiome. However, these may be early days. Given that there are 78 organs in the human body, the exact number of ageotypes remains an open question.

Looking from a different angle, tipping points for skin appear to occur at ages 30, 50, and 65. The immune system shows two bursts of decline, at 40 and 65. Interestingly, this coincides with the risk of Alzheimer's and Parkinson's, both of which increase around age 40 and rise substantially after 65. Cardiovascular risk grows from 16% to 40% between ages 40–59, then to 75% from age 60 onward, and to 85% by age 80.

These observations suggest that, from the point of maturity, the lifespan divides into phases lasting roughly 20 years.

Perhaps at each stage, damage accumulates until a tipping point is reached — but once reached, can it be reversed? No one knows. The best strategy for now may be to delay reaching those thresholds.

Brain wiring appears to undergo four major turning points across five phases. From birth to age 9, information flow is relatively slow. Between ages 9–32, possibly due to hormonal influence, the efficiency of neural connections increases, then begins decreasing between 32–66. Between 66–83 (the age range associated with dementia onset), connections within brain regions become stronger than connections between regions. Finally, between 83–90, connections between regions weaken further, and information flow becomes limited to a few remaining connection hubs.

Most people agree that they reach maturity by around age 29. With the speed of neuronal connections beginning to decline at 32, that leaves us, shockingly, with only about three full years at peak brain power. It seems one needs to start acting fast to slow the decline...

In a word, not by much. Fat digestion begins just as we swallow (not applicable to gelcaps, obviously), where digestive enzymes - lipases secreted at the back of the tongue start the process which continues in the stomach. The process goes into high gear in the duodenum, the uppermost section of the small intestine. Regardless of which form the fatty acids arrive in, they are broken down by families of lipases (for triglycerides and ethyl esters), phospholipases (for phospholipids), and carboxyl ester lipases, stimulated by bile. The net result is lysolipids, non-esterified fatty acids and 2-monoacylglocerols that form mixed micelles.

This emulsion is then taken up by the enterocytes lining the lower parts of the small intestine. In the enterocytes triacylglycerols are reassembled and packaged into lipoprotein particles called chylomicrons. These enter the lymphatic system before draining into the venous circulation. From there, some of the fat is delivered directly to peripheral tissues, while the remainder is taken up by the liver and repackaged into VLDL and LDL for further systemic delivery.

EPA+DHA appear fastest in plasma when ingested as non-esterified fatty acids, followed phospholipids, triacylglycerols, and ethyl esters. However, most fat is absorbed eventually regardless of the ingested form.

In short, various types of dietary fats or oil supplements are broken down and rebuilt so thoroughly during absorption that their original form (ethyl ester, triglyceride, or phospholipid) has not too much of a bearing on what ultimately reaches the tissues. Eventually, in people with normal digestion, more than 90% of ingested EPA and DHA will be absorbed regardless of the form they are ingested. It is prudent to take small doses of fats with meals to fully stimulate digestion and absorption.

This seemingly simple question doesn't have an answer everyone agrees on. While the FDA recognizes omega-6 linoleic acid (found in vegetable oils) and omega-3 linolenic acid (found in flaxseed and walnuts) as essential polyunsaturated fatty acids (PUFAs), it's actually the products made enzymatically from these two species that are in higher demand. Linoleic acid gives rise to omega-6 arachidonic acid, important for both membranes and inflammation, while linolenic acid - itself rarely, if ever, found in lipid membranes - is converted into the much more familiar, and also widely considered essential, EPA and DHA (of fish-oil fame). The problem with DHA, a main building block of the brain and retina, is that (except during pregnancy) it can't be made in sufficient quantities from linolenic acid, so it has to be consumed through food. Moreover, there's some indication that long-chain PUFAs like arachidonic acid, EPA, and DHA can be broken down into shorter species. So, loosely speaking, essential fats should probably be defined as two classes of PUFAs — omega-3 and omega-6, because there is no interconversion between the two in mammals.

To help resolve this taxonomy dispute, an alternative definition can be put forward. However experts feel about which particular fatty acids are essential, they all are fats that can undergo the non-enzymatic chain reaction of lipid peroxidation.

An isotope is a variant of a chemical element with the same number of protons but a different number of neutrons. Deuterium, for example, is a stable isotope of hydrogen: it has one proton and one neutron instead of just a proton. This subtle difference makes deuterium-carbon bonds harder to break, which is why D-PUFAs resist lipid peroxidation.

Peroxidation is the oxidation of lipids (fatty molecules) by reactive oxygen species, producing peroxides and other harmful by-products. In biology, lipid peroxidation is the most consequential form—it damages cell membranes and drives aging and age-related diseases.

Chemical isotopes have the same number of protons (and thus the same chemical identity) but different masses due to different numbers of neutrons. Heavier isotopes form slightly stronger bonds that are harder to break. Deuterium, the heavy isotope of hydrogen, slows down reactions that involve breaking C-H bonds—including the chain reaction of lipid peroxidation in cell membranes.

Aging is multifaceted and to slow it down will require a coordinated use of various interventions. That said, LPO stands out as a major contributor, largely due to the utter importance of lipid membranes to biology. 30% of all biochemical reactions happen in membranes. Neurons, mitochondria, the visual apparatus and many other things rely on membrane integrity for their function. And all that can be compromised, or destroyed, by LPO, pushing aging forward.

It increasingly looks so. Consider traumatic brain injury: the initial concussion produces a burst of lipid peroxidation, can years later yield Parkinson's, Alzheimer's, various dementias, ALS, MS or other ailments, indeed implicating LPO as a unifying mechanism behind these conditions.

People usually think about reduced membrane fluidity and impaired barrier function. This, however, pales in comparison with the downstream consequences. Oxidised fatty acids fragment into smaller pieces, which are often highly reactive. These can wreak havoc by reacting with one, or several, biomolecules, leading to accumulation of large insoluble waste deposits.

Both. Transition metals are genuinely Janus-faced. Enzymes need small amounts of them as essential cofactors, yet the very properties that make them useful inside enzymes make them hazardous when they're free in the cell. In particular, transition metals can generate reactive oxygen species (ROS), which in turn can trigger the radical chain reaction of lipid peroxidation.

They are incomparable. Antioxidants are tightly controlled and their levels in membranes cannot exceed certain fixed values, at best. At worst, they can do an about-face, turning into pro-oxidants. As smokers on antioxidants learned, at their peril, in a human clinical trial.

No. Suppose you have a wooden (= PUFA) fence. You'll need to keep stomping out (= antioxidant) fires (= ROS) approaching it to preserve it. Now suppose the fence is the same shape and size, but made of concrete… Antioxidants are used up stopping the fire, while D-PUFAs are just impervious.

No. Deuterium is a stable isotope of hydrogen.

No. Our bodies are well adapted to its natural presence (150 ppm, or 0.015% in sea water). Roughly, every 6500th atom of hydrogen is deuterium, giving 33 g deuterium per cubic metre of sea water. A typical human body contains about 1.5 g of deuterium, distributed across body water and organic molecules.

Given its low abundance, it takes a lot of effort to separate (concentrate) heavy water from fresh water. While various methods exist, they are all energy-hungry.

Affecting the chain at every step, the kinetic isotope effect "accumulates" along the entire chain, producing values far higher than those seen in the single-step reactions.

In a sense, they are both - and neither. Conventional drugs are foreign to the body, whereas both PUFAs and D-PUFAs are natural building blocks of cell membranes. Hydrogen and deuterium are simply isotopes of the same element, and deuterium is already present in cells. PUFAs and their D-PUFA counterparts behave identically in most chemical contexts, except in the LPO chain reaction. Pharmacotaxonomy is definitely lagging behind here. Perhaps a new, hybrid term should be used. Please share your ideas.

Yes. D-PUFAs travel through the body exactly as normal PUFAs do. As essential nutrients, PUFAs (and D-PUFAs) are absorbed in the small intestine, repackaged by liver and carried through the bloodstream to tissues throughout the body, first and foremost to those that need them most.

The daily turnover of PUFAs (and D-PUFAs) obtained from food is relatively slow in adult humans. Significant substitution of existing PUFAs in neuronal membranes from dietary sources such as fish oil typically requires weeks to months for noticeable changes, and often more than six months for substantial equilibration. For context, arachidonic acid (AA) replacement in the human brain has been estimated at approximately 0.3% per day, so to reach a meaningful level of brain D-ARA (about 25+% of the total ARA, see the book) should take around 3 months. DHA has a half-life of roughly 2.5 years. In practical terms, only about 4–5 mg of brain DHA is replaced daily, out of a total pool of approximately 5 grams. The efficiency of incorporation of supplemental PUFAs (including deuterated versions) depends on the levels of competing dietary PUFAs. For this reason, intake of deuterated PUFAs should ideally be accompanied by a substantial reduction in dietary consumption of ordinary (non-deuterated) PUFAs. This means minimizing high-PUFA foods such as fish oil supplements or mayonnaise. Achieving meaningful effects without such dietary restrictions would likely require multiple grams of D-PUFAs per day, which can be costly.

RCTs demonstrating prevention or treatment effects are, without question, the gold standard. But with an increasing number of drugs in R&D, a shrinking pool of subjects willing to enroll, and multi-million-dollar price tags, running them is becoming more and more challenging. Cutting corners — disregarding marginal benefit, safety concerns, irrelevance of surrogate endpoints, or methodological shortcomings — is not unheard of; just recall the anti-amyloid antibody trials.

RCTs' uniqueness as the ultimate proof of a good or bad effect may also be somewhat overstated. There was never an RCT linking smoking to cancer. A more tongue-in-cheek example is the famous absence of RCTs testing whether parachutes reduce injury when jumping from an airborne aircraft. Sometimes animal data, combined with observational studies, do yield valuable information on efficacy. As Prof. Gill Livingston puts it: "People always say that correlation does not equal causation, but, equally, it often does."

Recognizing these challenges, a movement has formed to give seriously ill patients access to promising experimental therapies. In the US, "right-to-try" laws were enacted in 41 states before becoming federal law in 2018. A newer wave — "Right to Try 2.0," now passed in 17 states — goes further still, allowing access to individualized experimental therapies that haven't even completed Phase I testing, extending the concept well beyond its original terminal-illness framing.

There is, in an aging body, a kind of low corruption. Not the dramatic failure of a single organ, but something quieter, creeping through like damp on the walls of an old colonial house. The immune system, once a disciplined sentry, grows careless with the years. It fires at shadows, hallucinating like AI, fighting ghosts. Inflammaging is what Claudio Franceschi called it in 2000.

The mechanism is not well understood, though it's clear that ever-increasing numbers of senescent cells (including deteriorating T-cells) are involved, constantly pressing the red "MAKE EICOSANOIDS" button to convert arachidonic acid into prostaglandins, leukotrienes, and the rest, feeding the smouldering inflammatory background. If an octogenarian twists his ankle, it swells, but the swelling recedes within a week or two. Yet inflammaging only rises. How can both exist at the same time, and how can inflammaging be resolved? That's the frontline of current research...

Through multiple interconnected mechanisms. Oxidized lipids are inherently pro-inflammatory, for example in the atherosclerosis setting. Some end-products of LPO, such as isoprostanes, mimic the structure of pro-inflammatory prostaglandins, so keeping them at low levels is beneficial. Other LPO end-products can irreversibly glue various biomolecules together, generating persistent inflammatory background. Lipoxygenases and cyclooxygenases convert arachidonic acid into a smorgasbord of predominantly pro-inflammatory eicosanoids. With age, these processes pile up, collectively contributing to "inflammaging". This pro-inflammatory "noise" can be mitigated by D-PUFAs.

No. Aspirin covalently reacts with COX enzymes, irreversibly "killing" them. Inhibitors of COX and LOS are enzyme-specific, and as a result often skew the important fine balance of various eicosanoids, such as in aspirin-sensitive asthma. D-PUFAs act across the board, softly down-regulating all COX and LOX enzymes. This dials down without distorting the delicate ratios.

Yes. Multiple animal studies demonstrate that D‑PUFAs can mitigate pathology across a range of disease models. It's important to remember, however, that no animal model fully predicts human disease. As Richard Klausner noted in 1998, "We have cured mice of cancer for decades—and it simply didn't work in humans."

Even so, the collective evidence from these models supports the idea that lipid peroxidation plays a central role in disease initiation and progression. Across neurological, retinal, mitochondrial, and other age‑related conditions, D‑PUFAs consistently prevent or markedly slow pathological changes. For example, several independent studies using distinct Parkinson's disease models—in cells, mice, and rats—found that D‑PUFAs robustly reduced disease‑related damage.

This topic is profound enough to warrant a book of its own. Although several tantalising observations are still awaiting publication, one paragraph from Breaking the Chains of Aging feels apt here:

…"If we were in a quiet lab, those of us with sharp enough hearing might even be able to perceive a commotion: the jiggling of lipids in the membrane, the popping of ROS, and the humming and soughing of the chain reaction, like rustling beetles in a matchbox. With a microscope that could livestream radicals in a ravaging LPO as blue dots, zooming in on a lipid membrane, we would see this coal black night sky with scattered, flickering ROS Death Stars. As the LPO speeds up and spreads wide, the number of stars skyrockets into myriads of bright blue dots, twinkling non-stop all over the visual field. Beautiful! And the constellation they seem to form is – wait a minute, it looks crab-shaped, - oh, no, can this be? – it is - Cancer"…

ARA makes up lipid membranes and so readily undergoes LPO. It is also processed by COX and LOX enzymes into eicosanoids, some of which reduce inflammation (like lipoxins) but most are pro-inflammatory (prostaglandins, etc). Some clinical trials and population studies fail to reveal a link between dietary ARA and inflammation. But things are rarely linear or black-and-white in biology, and are sometimes in conflict, due to various compensatory/bypass pathways. Aspirin-sensitive asthma (AERD), is an inflammatory disease. Yet removing pro-inflammatory PGs from the equation by inhibiting COXes with aspirin exacerbates the condition. How so? Well, the pool of arachidonic stays the same, but with less COXes to process it, LOXes proceed to make more leukotrienes, the bronchoconstrictors, which in this instance (and in some allergies) make things worse. Obviously, in this case, the level of arachidonic may matter, after all. Then there is also a poorly understood role of arachidonic in cancer...