Understanding Why Mole Rats Live Five Times Longer Than Expected

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The mole rat lives about 37 years which is about five times longer than expected for an animal of its size and type. Researchers at the Queen Mary University of London have learned more about why the mole rat lives so long.

The mole rat have fewer heart attacks. The mole rat adaptions to low oxygen environments is helps protect their hearts. Human are prone to heart injury by hypoxia and anoxia caused by blood occlusion during heart attacks. The naked mole rat heart avoids low oxygen damage.

Nature Communications – Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles.

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.

3 thoughts on “Understanding Why Mole Rats Live Five Times Longer Than Expected”

  2. Last time I looked at this almost ten years back, I was intrigued at how naked mole rats dodged cancer. I found something fascinating in that literature that crosses over with pain relief and cancer prevention in humans taking low-dose naltrexone (LDN). LDN boosts beta-endorphins (though the evidence here is maddeningly equivocal), met-enkephalin(MENK)/OGFR signaling and deeply affects TLR signaling and cell-cycle progression. Naltrexone blocks/acts via TLR4 signaling. LDN affects cell cycle progression via TLR7, a DAMP receptor for viral RNA like Covid/influenza. (This endorphin axis also crosses over into H2S metabolism – which drops with age – and resolvin/oxylipin (EET) production vital to inflammatory resolution and anti-inflammatory gasotransmitter production and balancing sympathetic/parasympathetic tone.)

    I’d encourage anybody investigating this topic to focus on the Nav1.7 endorphin/enkephalin axis. Given their hot, hypoxic environment, naked mole rats must be resistant to pain. They have a Nav1.7 (SCN9a/NAV26) mutation that makes pain receptors resistant to acid stress (protons). This boosts opioid sensitivity, boosts PENK in sensory neurons and depresses their serotonin responses.

    What’s not widely known is pro-inflammatory changes in sensory neurons are crucial for autoimmune damage to target organs like joints in arthritis or the gut in Crohn’s. This process also drives endometriosis and cancer development, yet sensory neuron growth/dysfunction has received relatively little attention. NaV1.7 in particular is involved in driving the growth of several cancers.

    Cancers rely internally on OH- (hydroxyls) to drive stemness. They have to pump out H+ (protons) into the intercellular space making the environment highly acidic – which provides a growth environment via Nav1.7 activation in several cancers (but wouldn’t in naked mole rats). This acidity fuels the MCT1/MCT4 shuttles bringing in lactate to feed the tumor’s Warburg effect – at the expense of tumor-suppressing enkephalin/endorphin production via normal Nav1.7 signaling.

    Humans have been under extraordinary evolutionary pressures to boost certain aspects of the enkephalin networks (esp. PENK B). In humans, butyrate production from gut flora also upregulates PENK A, the met-enkephalin (MENK) precursor (MENK is also potentially antiviral against influenza A-class viruses). I believe butyrate also boosts pro-resolving LXA4 in addition to inducing Nrf2 (also a target of several resolvins) and stimulating IAP, which detoxifies inflammation in the gut, preventing insulin resistance. The EFA ALA also inhibits soluble epoxide hydrolase, which degrades oxylipins. ALA is short in modern human diets, along with anti-inflammatory GLA

    In short, changes in human diet and environment shift us to a pro-inflammatory state that favors diabetes, cancer and shortens our lifespans.

    [PMID 28074005]
    [PMID 22174253]
    [PMID 28850427]
    [PMID 26634308]
    [PMID 27529686]
    [PMID 24959274]
    [PMID 26386152] (benzonatate)
    [PMID 28118359] (AMPK)
    [PMID 24809977]
    [PMID 28254884] (Sema3a)

    Couldn’t get a damn person at MD Anderson in 2016 to pay a lick of attention to any of this promising research. Even today when you blurt out, “low-dose naltrexone,” most oncologists clutch their bank accounts and run screaming in the other direction. Check out the METABLOC protocol for metastatic cancer: LDN, hydroxycitrate and I.V. alpha lipoic acid (aka thiotic acid). This tackles the Warburg effect head on and I think the sensory neuron angle is important in explaining the effect. I might also add butyrate for tumor epigenetics, sulforaphane, EPA/DHA for resolvins and benfotiamine.

    Of course, none of this is without side effects or other risks.

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