Anyone know if Joe is still alive? The last I heard he was 41 about a year ago. You never know with these old timers…
Here’s the latest paper on Naked Mole Rats (NMRs) focusing on their unique immune systems.
http://www.nature.com/articles/s41467-024-47264-x
Also, this is the professor working with Joe and performing on-going research into the naked mole rat’s longevity.
The key features of NMRs -
The researchers found that naked mole rats are able to more strongly inhibit the metabolic process of the senescent cells, resulting in higher resistance to the damaging effects of senescence.
The key is a protein called c-GAS which, unlike in humans where it can hinder DNA repair, has evolved in the mole-rat to actively help mend damaged DNA, keeping their genetic code intact.
Researchers are excited by this finding, and are hoping to “reverse-engineer” the mole-rat’s unique biological process. Very interesting.
Speaking of NMR consuming Tubers(i.e. root veggies such as sweet potatoes) and subterranean low sunlight vitamin D independenr metabolic pathways:
Eating tubers helps naked mole rats achieve exceptional longevity primarily through their effects on metabolism, nutrient intake, and cellular health���. Tubers are low-protein, low-methionine plant foods, and naked mole rats have adapted to thrive on this diet, which closely resembles the dietary interventions that extend lifespan in other model organisms��.Nutritional Composition and Metabolic EffectsTubers are rich in complex carbohydrates and fiber, but low in protein and particularly low in the amino acid methionine��.
Naked mole rats show plasma profiles with low levels of circulating methionine, a feature that mimics the benefits seen in methionine-restricted diets proven to extend lifespan in mice, rats, and other animals�.Their diet supports a low metabolic rate and helps prevent age-related metabolic decline, contributing to the maintenance of stable physiological functions well into old age��.
Impact on Aging and Health: Methionine restriction from tuber diets is linked to lower oxidative stress, resistance to cancer, and delayed onset of age-related diseases in naked mole rats��.Naked mole rats retain youthful metabolic profiles throughout their lives, similar to animals on caloric restriction or extended fasting periods�
Their natural underground diet of tubers also promotes a stable gut microbiome, further supporting health and longevity�.
Several compounds in tubers are linked to enhanced DNA repair and longevity, both via direct biochemical action and through antioxidant effects that protect DNA from damage.
Key Tuber-Derived Compounds
Caffeoylquinic acids (chlorogenic acids): Potent antioxidants found in many tubers that stimulate cellular repair of oxidative DNA damage, helping maintain genome integrity.
Phenolics and flavonoids: Broadly present in tubers such as potatoes, sweet potatoes, and yams, these compounds scavenge free radicals and support excision repair mechanisms, decreasing mutation rates and protecting cells against aging.
Beta-carotene and Vitamin C/E: Vitamins abundant in tubers work as antioxidants, reducing oxidative stress and aiding enzymatic DNA base repair, thus contributing to longevity.
Terpenoids and glycosides: Select tubers harbor bioactive terpenoids and glycosides found to extend lifespan in animal models, partially by upregulating genes involved in stress resistance and DNA repair.
Mechanisms Promoting LongevityAntioxidant compounds reduce DNA damage from metabolic processes and environmental stress.
Some tuber-derived molecules actively stimulate cellular DNA repair pathways, including base excision and homologous recombination, crucial for maintaining stable genetic function throughout aging.
These compounds result in a lower incidence of cancer and age-related diseases, as seen in animal models and suggested by naked mole rats’ exceptional lifespan.
An Okinawa diet!!
Nick this is very interesting. Can you share what the sources are for these two posts above?
Source: https://x.com/MartinBJensen/status/1976660387111342160
If you’re interested in the science of healthspan and longevity, you’ve likely heard of the naked mole rat, a remarkable outlier among mammals that defies the laws of biologic aging. For nearly 30 years, we didn’t know what accounted for this phenomenon, but a compelling new report sheds light on a pathway that was only discovered in 2012, awarded the Lasker Prize in 2024, and is now the target of many clinical trials. This edition of Ground Truths is about the convergence of two exciting life science discoveries and how they may influence the future of medicine.
Background: Two Threads of Life Science Converge
By the late 1990s it was noted that there was something unusual about the lifespan of naked mole rats. In 2002, Drs. Rochelle Buffenstein and Jennifer Jarvis, comparative biologists, published “ A New Record for the Oldest Living Rodent” for the naked mole rat, living over 27 years, about 5 times the maximal lifespan of mice or rats. In the past 2 decades since this discovery, much work done to understand their longevity and remarkable resistance to age-related diseases. Their heart, kidneys, liver, eyes and bones remain youthful. Cognitive function is preserved and they do not develop cancer (only 5 cases in over 3,000 necropsies). Some have lived up to 39 years of age. It has been shown that the naked mole rat lifespan defies Gompertz’s law for not having an exponentially increasing risk of death as they get older—the naked role rat is considered a “non-aging mammal.” Their existence is almost completely underground, moving around in tunnel systems. They are certainly not attractive! (Figure below) They are hairless, buck-toothed, wrinkly, and can survive without oxygen for 18 minutes. Known as extreme xenophobes, they only seem to die when they beat each other up. Owing to the unique features of healthspan and lifespan, they are considered the supermodel organism for understanding these critical biological features.
But until now, we didn’t know the underlying mechanism for how naked mole rats lived so long and so healthily. This week, in Science, Yu Chen and colleagues from China published a compelling case for what explains the naked mole rat story.
Before we get to that, let’s go to a major basic science discovery that was awarded the 2024 Lasker Prize (considered pre-Nobel). Last year’s basic medical research prize recipient was Dr. Zhijian Chen of the University of Texas, Southwestern, for the discovery of cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase (yes a mouthful, thank goodness for acronyms). In back to back papers in Science in 2012 and 2013, Chen and colleagues identified and described cGAS and the pathway. It serves as a danger sensor, predominantly present in the cell cytoplasm, detecting penetration of foreign DNA from a virus or bacteria, or damaged DNA in the cell. Once danger is sensed, cGAS is activated and through cGAMP there is activation of STING, which stands for the stimulator of the interferon gene. This critical step leads to production of Type I interferons, a principal component of our innate immunity (simplified Figure below). Recall that with SARS-CoV-2 infection, Type 1 interferon, our first line of defense, provided critical protection, such that people with autoantibodies to type 1 interferon were highly vulnerable to severe, life-threatening Covid.
You can also see this pathway’s role in promoting inflammation, cell senescence, and death. Since the discovery in 2012, the cGAS-STING pathway has been implicated in many autoimmune and age-related inflammatory diseases, including cancer and neurodegenerative.
“Solved” seems optimistic. The claimed effects in mice seem impressive (without reading the paper, which I can’t access). On the other hand, there’s no lifespan claim for mice, possibly due to resource constraints.
Papers:
Is there anything we can do now to enhance DNA repair?
A little… but you’re probably already doing most of these things. I know of at least one company that is working on bringing drugs to market that protect DNA from double-strand breaks.
Here is a prioritized summary of the major interventions we discussed for enhancing DNA repair/genome stability — ranked by strength of evidence, effect size (where reported), and relevance to healthy human populations. I’ll include for each: effect size (if known), evidence quality, key caveats, and a “priority score” (relative) to help you decide how to allocate effort/attention in your optimisation framework.
| Rank | Intervention | Reported Effect Size* | Evidence Quality & Quantity | Key Caveats | Priority Score† |
|---|---|---|---|---|---|
| 1 | Micronutrient optimisation (e.g., folate/B12/zinc/vitamins C/E/selenium) | Moderate but variable: e.g., one study showed increased vitamin C supply reduced 8‑oxodG ~2‑fold in sperm DNA under low‑intake conditions. | Fair: Several human observational & intervention studies, but many with mixed results, short durations, surrogate endpoints only. | Most data relate to deficiency→adequacy transitions, not supra‑normal supplementation. Effects differ by baseline status & exposure load. | ★★★★☆ |
| 2 | Polyphenol‑rich diet / phytochemicals(berries, anthocyanins, curcumin, other flavonoids) | Small to moderate: Review shows consistent reductions in DNA damage markers in human diet studies (Comet assay) but effect sizes often modest and heterogeneous. | Moderate: Many human dietary interventions (though few RCTs), many cell/animal studies. | Bioavailability issues, dose/compound heterogeneity, many studies in healthy young adults with low baseline damage load. | ★★★☆☆ |
| 3 | Sleep / circadian alignment (ensuring proper sleep to support DNA repair) | Indirect effect, but mechanistically strong: studies show sleep deprivation increases DNA damage and reduces repair gene expression. | Good mechanistic evidence, less human RCTs for “sleep optimisation → DNA repair” endpoint. | Hard to quantify “how much better” repair gets; likely foundational rather than “boost” only. | ★★★★☆ |
| 4 | Melatonin supplementation | In one human RCT (40 night‑shift workers), 3 mg melatonin for 4 weeks led to ~1.8‑fold increase (95% CI 1.0‑3.2) in urinary 8‑OH‑dG (marker of oxidative DNA damage repair) during day sleep. p ≈0.06 (borderline). | Moderate but limited: Only one small RCT in a specific population (night‑shift workers). Many other mechanistic/cell studies. | Specific population (shift workers) with suppressed melatonin; effect in general healthy population unclear. Dose/long‑term safety/efficacy unknown. | ★★☆☆☆ |
| 5 | Targeted DNA‑repair drugs / advanced agents (e.g., PARP activators, NAD+ precursors, sirtuin modulators) | Preclinical only (cell & animal) showing enhancement of repair pathways (e.g., NAD+ dependent PARP activity) but no robust human trial data for healthy individuals. | Weak: mechanistic data strong, human outcome data basically absent. | Unclear safety, dose, long‑term effects; potential off‑target/unintended consequences. | ★☆☆☆☆ |
† Priority Score: ★☆☆☆☆ = lowest, ★★★★☆ = higher priority
For more than 1,000 years, the Inupiat people of Alaska have hunted bowhead whales in the Arctic Ocean. Over the centuries, they grew to appreciate the long lives of the animals, the longest-living mammals on Earth. Generations of hunters could recognize the same individual at sea. Inupiat captains have told researchers that a bowhead whale lives two human lifetimes.
Scientists now suspect that bowheads can live even longer than that. Some whales caught in the late 1900s had old harpoon points lodged in their blubber that dated to the mid-1800s. By measuring the molecular damage that accumulates in the eyes, ears and eggs of bowhead whales, researchers have estimated that bowheads live as long as 268 years.
A study published in the journal Nature on Wednesday offers a clue to how the animals manage to live so long: They are extraordinarily good at fixing damaged DNA.
The new study was led by Vera Gorbunova and Andrei Seluanov, a married couple who both work at the University of Rochester and study long-lived mammals such as bats, beavers and naked mole rats, along with bowhead whales. They and their colleagues are uncovering many molecular adaptations that extend animal lives. These species, the research shows, are gaining years thanks to increases in the levels of certain proteins and subtle changes in how these proteins work with others.
“We’re not talking about new genes,” Dr. Seluanov said. That finding raises the possibility that similar changes could be reproduced in humans to extend our own healthy life span. “We need to just tweak our system a little bit to resemble what we’ve found in naked mole rats or bowhead whales,” Dr. Seluanov said.
As it turns out, bowhead whale cells produce large amounts of a protein called CIRBP. Its job is to speed up the production of other proteins that protect against cold-triggered damage to cells.
Dr. Gorbunova and Dr. Seluanov also noticed a lot of CIRBP floating around the whale’s DNA as well. They found a single study, published in 2018, suggesting that CIRBP might also help repair DNA. Indeed, when Dr. Gorbunova and Dr. Seluanov inserted the bowhead CIRBP gene into human cells, the rate of DNA repair in those cells doubled.
The DNA-fixing protein, and the gene that produces it, appear to be key to the bowhead’s longevity. Over an animal’s lifetime, damaged DNA builds up throughout its body, leading to many ailments, not just cancer. When the scientists engineered the bowhead’s CIRBP gene into fruit flies, those flies lived longer than those with the normal insect version of the gene.
Read the Full story: Life Lessons from (Very Old) Bowhead Whales (NY Times)
And we can focus on preventing DNA damage…
Above ChatGPT claims that increased urinary 8‑oxodG is a marker of increased DNA repair but I think that’s misleading. Yes increased 8‑oxodG in the urine is a marker of more DNA having been repaired, but that doesn’t necessarily indicate improved DNA repair. It might as well just mean there was more DNA to repair rather than your body having been repairing more of the damage that is present. As an example, if your DNA damage remains constant but your body suddenly starts repairing 50% more of it, then urinary 8‑oxodG would increase about 50%. However if you suddenly have 50% more DNA damage but are repairing the same proportion of the damage as before, then urinary 8‑oxodG would also increase by about 50%. But in the latter case, the increase isn’t reflecting improved repair but more damage.
This YAK study looking at CIRBP is worth a look:
https://www.mdpi.com/2218-273X/15/6/759
shows that rapamycin and CIRBP share common mechanisms
Essentially: Yaks “over-express” CIRBP for cold adaptation. The study used Rapamycin as a “positive control” Finding: if they knock down the Yak’s CIRBP expression then Rapamycin will come to the rescue and replicate the lost CIRBP benefits
Per Grok 4.1
Title: CIRBP Enhances the Function of Yak Cumulus Cells by Activating AMPK/mTOR-Mediated Mitophagy
Authors: Rui Zhang, Yan Cui, Yangyang Pan, et al.
Journal: Biomolecules (Volume 15, Issue 6, Article 759)
Publication Date: 24 May 2025
DOI: 10.3390/biom15060759 (Open access; full text available on MDPI and PMC)
Mild hypothermia (32 °C) mimics cold stress:
CIRBP overexpression:
Rapamycin (mTOR inhibition) as positive control:
Pathway confirmation:
This is currently the only published study directly linking CIRBP to mitophagy regulation in any cell type, and it highlights a novel “rapamycin-like” endogenous pathway.
