Negligible Senescence and Exceptional Genome Maintenance in Naked Mole-Rats
Studies of the comparative biology of aging involve mapping the genetics and cellular biochemistry of exceptionally long-lived species in search of significant differences, when compared with both humans and shorter-lived species. The hope is that findings may inform human medical research, and at best could lead to new directions for the development of therapies to address aspects of aging. Species of interest include whales, for longevity and exceptional cancer resistance given their size, elephants, also for unusual cancer resistance, and naked mole-rats, which live far longer than similarly sized rodent species, and are near immune to cancer.
Today I'll point out a couple of recent papers from research groups investigating the naked mole-rat. It has for a while now been generally accepted that naked mole-rats are negligibly senescent. This is a blanket and in practice fairly loosely applied term indicating that members of a species show little signs of aging across most of a life span (for some definition of "little" and "most"), with a sudden and short decline at the end. This is very unlike the human life course, which takes the form of an exponential decline that starts comparatively early, in the middle of life.
Aging in this context has a precise definition: it is the rise in mortality rate over time due to intrinsic causes, the accumulation of cell and tissue damage resulting from the normal operation of cellular metabolism. If mortality rate remains roughly static over time in a population, then its individuals are not aging - which can in principle be the case at any mortality rate, high or low, but agelessness coupled with a high mortality rate seems more of a curiosity than a useful phenomenon, where it does occur. The naked mole-rats exhibit the low mortality option, of course. The first paper below provides evidence to back up the assertion that naked mole-rats don't just seem negligibly senescent, but actually are negligibly senescent.
The second paper looks at stochastic mutation rates across the life span, one of the many areas of biochemistry that researchers believe is important to aging. Mutation incidence is also a determinant of cancer risk - cancer is a numbers game, with every mutation that occurs having a tiny chance to be of a type that can give rise to an unrestrained, cancerous cell. Everything connected to aging looks better in a naked mole-rat, and that includes low mutation rates and highly effective DNA repair. Clearly some of those measures are secondary to the root cause reasons as to why the species ages so lightly until the very end of life - they can't all be root causes.
DNA maintenance may fall into either category, though the present consensus places it a meaningful contributor to the declines of aging. However, it remains the case that definitively determining the relative importance of specific contributions to the outcomes of aging is a challenge. These questions will probably remain open until biotechnology is applied to block or eliminate various likely mechanisms in naked mole-rats, or recreate those same mechanisms in mice, in order to observe the outcome. Theorizing and mapping can only take us so far at the present time.
Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age
The naked mole-rat is a strictly subterranean, mouse-sized rodent and is one of only two known eusocial mammals. The longest-lived rodent, it is recognized as an animal model of biogerontological interest, with a maximal lifespan of more than 30 years in our captive care. This maximum lifespan is five-fold greater than predicted allometrically for a 40g rodent. Beyond lifespan, the physiological declines that accompany advancing age in most mammals fail to manifest in naked mole-rats. Breeding females show no menopause, retaining high fertility even at ages past 30 years. Neurogenesis is also prolonged and may continue for at least two decades, and over a similar time course, no significant changes in cardiac function, body composition, bone quality, and metabolism are evident. Age-associated chronic diseases such as cancer are also rare. Within the cell, proteasome function, as well as mitochondrial mass, gene expression, and protein expression are maintained with age.
The concepts of mortality and physiological decline associated with aging can be connected within the mathematical framework of the Gompertz-Makeham law of mortality. Mortality hazard increases exponentially with age, presumably due to intrinsic age-related physiological declines. While naked mole-rats are already noted as exceptionally long-lived, this status relies on small-sample-based estimates, leaving much uncertainty as to how exceptional their longevity may truly be and how they differ from other mammals with respect to the Gompertz-Makeham aging framework. Here, we compiled a large, historical dataset of naked mole-rat lifespans using records kept throughout the ~35 year maintenance of our collection. With over 3000 data points, we constructed survival curves and performed analyses of age-specific hazard. In these analyses, this mouse-sized rodent exhibited no increase in mortality hazard, that is, no Gompertzian aging, across its full, as-yet-observed, multi-decade lifespan. This life-history trend is unprecedented for mammals.
Genome Stability Maintenance in Naked Mole-Rat
DNA damage caused by environmental stress and normal metabolic processes occur daily at a frequency raging from 1,000 to 1 x 10^6 per living cell. As a result, only 0.00017% of the human genome consisting of 3 x 10^9 base pairs is damaged, but lesions in essential genes, such as the genes that code for tumor-suppressor proteins, can significantly disturb cellular function. The efficient DNA repair mechanisms that counteract DNA damage accumulation substantially contribute to genome stability maintenance, which is one of the crucial cellular functions. Accumulation of DNA lesions and mutations increases the risk of cancer and is related to aging.
Only a few experimental studies have focused on the search for a correlation between the activity of DNA repair systems and maximum lifespan. The complexity of these studies and their controversial findings may stem from both the imperfect methods used for activity assessment and improper selection of model systems. The naked mole-rat (NMR) is one of the most promising models used to study genome maintenance systems, including effective repair of DNA damage. The lifespan of the NMR can reach 32 years, ten times longer than that of the mouse. For most of its lifespan (at least 80%), this animal shows no signs of aging and retains the ability to reproduce. It possesses a very efficient mechanism of resistance to cancer, including cancer induced by different stressors.
The naked mole-rat draws the heightened attention of researchers who study the molecular basis of lengthy lifespan and cancer resistance. Despite the fact that the naked mole-rat lives under genotoxic stress conditions (oxidative, etc.), the main characteristics of its genome and proteome are a high stability and effective functioning. Replicative senescence in the somatic cells of naked mole-rats is missing, while an additional p53/pRb-dependent mechanism of early contact inhibition has been revealed in its fibroblasts, which controls cell proliferation and its mechanism of ARF-dependent aging. The unique traits of phenotypic and molecular adaptations found in the naked mole-rat speak to a high stability and effective functioning of the molecular machinery that counteract damage accumulation in its genome.