The Mysteries of Naked Mole-Rats: An Investigation into Extreme Longevity through Metabolomic and Immunological Approach
The naked mole-rat (Heterocephalus glaber) is one of the most remarkable animals in the animal kingdom. Its lifespan exceeds 37 years, which is more than ten times longer than that of other rodents, including the laboratory mouse (Mus musculus). In this piece, we examine the immune system and metabolomic signature of these fascinating animals to learn more about the mechanisms underlying their extraordinary longevity and resistance to age-related illnesses.
The Metabolomic Signature of Naked Mole-Rats:
A groundbreaking study utilizing mass spectrometric metabolomics has shed light on the metabolomic differences between naked mole-rats and mice at various ages. Strikingly, the variations between the two species outweighed age-related alterations, affecting essential metabolic pathways involving amino acids, bile and fatty acids, monosaccharides, and nucleotides.
Of particular interest were metabolites associated with pro-health and anti-aging effects in mice, such as α-tocopherol (vitamin E) and polyamines (cadaverine, N8-acetylspermidine, and N1,N8-diacetylspermidine). These compounds were found to be significantly more abundant in naked mole-rats than in mice. Notably, the age-related decline observed in mice for spermidine and N1-acetylspermidine levels did not occur, and in some cases, was reversed in naked mole-rats. This metabolomics analysis provides a foundation for testable hypotheses aiming to explain the exceptional longevity of naked mole-rats.
The Longevity and Unique Characteristics of Naked Mole-Rats:
Naked mole-rats, the longest-lived rodents, have a maximum lifespan exceeding 37 years. Unlike other rodents, they exhibit a delayed aging phenotype, resist age-related functional decline and diseases, and rarely develop cancer and Alzheimer’s disease. Living in hypoxic underground colonies in East Africa, naked mole-rats showcase remarkable tolerance to low oxygen levels, further fueling scientific interest.
This review consolidates findings on the ecology, hypoxia tolerance, longevity, delayed aging, and cancer resistance of naked mole-rats. Additionally, we explore potential mechanisms contributing to their healthy aging, addressing current issues and future perspectives in unraveling the mysteries behind their extended lifespan.
The Immune System of Naked Mole-Rats:
The immune system, a complex network crucial for maintaining health span and life span, plays a pivotal role in the unique characteristics of naked mole-rats. Despite their small size, these subterranean-dwelling creatures exhibit an extended lifespan and exceptional cancer resistance. To understand these phenomena, researchers conducted single-cell RNA-sequencing (scRNA-seq) to map the immune system of naked mole-rats and compare it to the short-lived, cancer-prone mouse.
Surprisingly, the study revealed a high myeloid-to-lymphoid cell ratio in naked mole-rats, including a novel, lipopolysaccharide (LPS)-responsive granulocyte cell subset. Strikingly, naked mole-rats lack canonical natural killer (NK) cells, challenging our current understanding of mammalian immunity. Comparative genomics analyses support this finding, indicating a lack of an expanded gene family controlling NK cell function in naked mole-rats.
The study of naked mole-rats’ metabolomic and immunological features has revealed peculiar features of their biology that support their extraordinarily long lifespan, postponed aging, and resistance to cancer. These discoveries open up new avenues for investigation and may result in significant advancements in the study of immunity and aging in addition to expanding our knowledge of the fascinating world of naked mole-rats.
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