Recent Updates on Naked Mole Rat Research

Comparative study of the biology of aging in species with widely divergent life spans is undertaken by a number of groups in the broader research community. The idea here is that, especially in the case of similar species that nonetheless have very different life spans, chasing down the root causes of these differences will help identify the most important aspects of the biology of aging in our species. This is a very different approach to the problem of aging to the strategy I favor, which is to skip over much of this investigation of the details in favor of focusing on ways to repair known differences between old tissue and young tissue, as exemplified by the SENS research programs.

In any case, it turns out that a great deal of the interaction between metabolism and aging is very similar in many species, and the specific mechanisms present today are inherited from a common but distant evolutionary past, such as the response to calorie restriction that increases health and longevity. Given this, a better understanding of differences in aging between various types of mammal should in turn help to inform research aimed at understanding or treating human aging. In the most optimistic viewpoint the study of aging in diverse species may yield treatments based on importing or mimicking beneficial aspects of non-human biochemistry. Whether or not that turns out to be an effective path forward is up for debate. It depends greatly on the details of any specific attempt and it is really far too early in this process to do more than speculate on that front.

Naked mole rats are one of the better studied species with respect to the comparative biology of aging. From a taxonomic point of view they are not so very distant from mice of a similar size and yet live up to nine times longer. Why? Further, and of perhaps greater interest to today's medical research community, where funding is very biased towards treatment of specific named diseases and there is comparatively little money for aging research, naked mole rats appear to be essentially immune to cancer. Thus there is a growing interest in this species in many quarters. The research group run by João Pedro de Magalhães, who you might recall published a call to action on life extension research earlier this year, recently released an open online database for the naked mole rat genome:

The Naked Mole Rat Genome Resource: facilitating analyses of cancer and longevity-related adaptations.

The naked mole rat (Heterocephalus glaber) is an exceptionally long-lived and cancer-resistant rodent native to East Africa. Although its genome was previously sequenced, here we report a new assembly sequenced by us. We analyzed the annotation of this new improved assembly and identified candidate genomic adaptations which may have contributed to the evolution of the naked mole rat's extraordinary traits, including in regions of p53, and the hyaluronan receptors CD44 and HMMR (RHAMM).

Furthermore, we developed a freely-available web portal, the Naked Mole Rat Genome Resource, featuring the data and results of our analysis, in order to assist researchers interested in the genome and genes of the naked mole rat, and also to facilitate further studies on this fascinating species. This resource is open source and the source code is available at: https://github.com/maglab/naked-mole-rat-portal.

Meanwhile, other researchers are looking for mechanisms to explain how it is that naked mole rats maintain relative levels of undamaged proteins, or proteostasis, far more efficiently throughout their life spans than other rodent species. Aging is characterized by the accumulation of damage and change in cell structures and relative levels of circulating proteins, and slower or more negligible aging is associated with more effective maintenance of proteostasis over time. This doesn't say too much about cause and effect when stated at the high level in this way: it is just what can be observed.

In the research quoted below scientists are on the trail of a noteworthy difference in naked mole rat damage control mechanisms, structures called proteasomes within the cell responsible for breaking down damaged or otherwise unwanted proteins. In naked mole rats the proteasome is more effective at its job as well as being more resilient to interference and damage, and these researchers have found that they can cause proteasomes from other mammalian species to perform just as well by importing a grab bag of proteins and structures from naked mole rat cells. At this point it remains to be seen as to what the crucial factors are, but I can't imagine it'll take long to pin that down:

Factor in naked mole rat's cells enhances protein integrity

A factor in the cells of naked mole rats protects and alters the activity of the proteasome, a garbage disposer for damaged and obsolete proteins. The factor also protects proteasome function in human, mouse and yeast cells when challenged with various proteasome poisons, studies showed. These proteasomes usually rapidly stop functioning, leading to the accumulation of damaged proteins that further impair cell function, contributing to the vicious cycle that leads to cell death. "I think this factor is part of an overall process or mechanism by which naked mole rats maintain their protein quality."

Generally, as an organism ages, not only are there more damaged proteins in need of disposal, but the proteasome itself becomes damaged and less efficient in clearing out the damaged proteins. As a result, protein quality declines and this contributes to the functional declines seen during aging. Enhancement of protein quality, meanwhile, leads to longer life in yeast, worms, fruit flies and naked mole rats.

A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition

The naked mole-rat maintains robust proteostasis and high levels of proteasome-mediated proteolysis for most of its exceptional (~ 31 years) life span. Here, we report that the highly active proteasome from the naked mole-rat liver resists attenuation by a diverse suite of proteasome-specific small molecule inhibitors. Moreover, mouse, human, and yeast proteasomes exposed to the proteasome-depleted, naked mole-rat cytosolic fractions, recapitulate the observed inhibition resistance, and mammalian proteasomes also show increased activity.

Gel filtration coupled with mass spectrometry and atomic force microscopy indicates that these traits are supported by a protein factor that resides in the cytosol. This factor interacts with the proteasome and modulates its activity. Although HSP72 and HSP40 (Hdj1) are among the constituents of this factor, the observed phenomenon, such as increasing peptidase activity and protecting against inhibition cannot be reconciled with any known chaperone functions. This novel function may contribute to the exceptional protein homeostasis in the naked mole-rat and allow it to successfully defy aging.

Comments

Is damage to the proteasome protein disposal machinery a type of damage separate to those outlined in the SENS proposal? Would it also need to be taken care of?

Posted by: Jim at September 1st, 2014 7:45 PM

What the researchers did here with inhibitors bears little semblance to what happens in aging. Proteasome inhibitors exist for other uses, so are a tool that researchers can pull of the shelf when wanting to know "what happens here if the proteasome stops working?"

http://en.wikipedia.org/wiki/Proteasome_inhibitor

The proteasome is a part of a larger system of flagging and routing proteins, and that system as a whole declines with aging. This may be due to damage to portions of that system or it may be a reaction to other forms of cellular damage. In the case of actual damage to proteasomes, of which the cell has many, if that is in fact the issue then the situation looks more like a case of not enough proteasome turnover taking place, which sounds like a garbage catastrophe due to rising levels of general damage overwhelming the necessary machinery for dismantling cell structures (such as the lysosome).

Something on damage to proteasomes themselves, which blames cross-links, molecular damage, and reduced gene expression of the proteins making up a proteasome:

http://www.ncbi.nlm.nih.gov/pubmed/12200039

Something on decline of the recycling system of which the proteasome is a part:

http://www.ncbi.nlm.nih.gov/pubmed/21324320

It is clear that as in many areas, more work is needed to give better answers to the open questions. Implementing portions of SENS is probably the fastest way to find out what are the important contributions to proteasomal dysfunction, but that is true of most age-related changes in cells. The other approaches to obtaining answers will produce a more encompassing picture in the end, but will take much longer and far more in the way of resources.

Posted by: Reason at September 1st, 2014 8:18 PM

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