Reduced Levels of Myc Regulator Mtbp Modestly Extend Life in Mice
Despite the fact that we stand within reach of human rejuvenation, to be achieved through repair of the known forms of biological damage that cause aging, the majority of research into aging and longevity has next to nothing to do with that goal. It is instead a slow and painstaking process of mapping, an attempt to understand how exactly cellular biology produces aging, at the detailed level of genes and protein interactions. It takes years of work to obtain a useful amount of new information about the role of one specific gene, and there are thousands of genes of interest, formed into networks. There are many ways to influence the behavior of these networks - pick a gene, alter its structure or the amount of protein produced, and the entire network is affected. Pick another gene and the network reacts in a different way.
This is why those researchers who believe that the only way forward is to produce the map, and then use it to alter the operation of metabolism to slow the rate at which it causes aging, generally have a pessimistic view of the future of medicine to enhance human longevity. There is too much work, too little funding, and too few researchers. Further, the gains are modest at best, on a par with the results of practicing calorie restriction or regular exercise. This is why we need a revolution in the field of aging research, one that directs far more resources towards initiatives like SENS rejuvenation research: instead of prioritizing mapping, rather prioritize the application of what is already known about the forms of cell and tissue damage that causes aging, prioritize building the envisaged repair biotechnologies that should result in rejuvenation. Clear the damage in the metabolism we have rather than trying to build an incrementally better form of human being - it will be faster, cheaper, and more effective by far. We don't have all the time in the world to get this job done.
This is a fight that continues. Damage repair is a minority concern in aging research, despite the recent interest and funding for senescent cell clearance. The vast majority of aging research looks exactly like the example presented here, which is to say a matter of exploring genetic alterations known to modestly alter the course of aging in short-lived species. Researchers move step by step and protein by protein by following relationships and correlations. In this case the starting point is established knowledge: when gene expression of Myc is inhibited, the outcome is modestly slowed aging in mice. Further, Mtpb is known to be a regulator of Myc activity, one of the many ways in which proteins can be related to one another. Thus the researchers followed this link to carry out a study on Mtpb and aging in mice, showing that reduced levels of Mtpb also slow aging in mice.
As is usually the case when the effects of two related genes are explored, the result is only similar to the outcome for reduced levels of Myc, not the same. There are always differences: genes and proteins form large networks of cascading interactions, and this network is the machine to keep in mind, built of intricate repeated molecular interactions extending over time. Tinkering with different parts of the network will inevitably alter its operation in somewhat different ways. As you might imagine, at this pace, and at the present size of the research community, it will take a very long time indeed to make meaningful progress towards the grand map of metabolism and aging. No-one alive today should be placing any great hope of a longer healthy life achieved through life-extending medication on such work. If our lives are extended, it will come from the engineering approach exemplified by the SENS portfolio of proposed rejuvenation therapies.
Aging is a complex biological process controlled by both environmental and genetic factors; however, twin studies suggest 20-30% of lifespan variation is genetic. Altering the activity or expression of specific genes significantly impacts lifespan in animal models. For example, increased expression of the protein deacetylase Sirt1 is known to slow the effects of aging and increase lifespan. In contrast, reduced levels of the oncogenic transcription factor c-Myc (Myc), due to heterozygosity, was recently reported to significantly increase longevity in mice. Myc is estimated to transcriptionally regulate 10-15% of the genome. While Myc has been implicated in processes such as stem cell maintenance, differentiation, and apoptosis, Myc transcriptional activity is closely linked to cell-cycle progression and the vast metabolic machinery required for cellular proliferation. Notably, Myc regulates mitochondrial biogenesis, providing sufficient mitochondria to maintain increased cellular metabolism. Myc also increases overall protein synthesis, a known modulator of longevity, through regulation of genes that control ribosomal assembly.
Based on the broad control Myc exerts over cellular processes relevant to aging and the recent publication directly linking Myc to longevity, proteins that regulate Myc represent potential modulators of the aging process. We recently reported that Mtbp is a Myc transcriptional co-factor. In mice, Mtbp heterozygosity resulted in reduced Mtbp protein expression without altering Myc levels, and this inhibited Myc-mediated transcriptional activation of target genes, proliferation, and B cell lymphoma development. Knockdown of Mtbp expression delayed cell cycle progression. In contrast, elevated Mtbp expression increased the number of cells in S-phase and enhanced Myc-mediated transcription and tumor development. These data indicate Mtbp is a positive regulator of Myc transcriptional activity and downstream biological functions. Thus, we tested whether reduced Mtbp expression would alter aging in similar ways to decreased Myc expression.
Since Myc+/- (heterozygous) mice have increased longevity and we have shown that Mtbp is a positive regulator of Myc, we investigated the contribution of Mtbp to longevity using a cohort of littermate-matched Mtbp+/+ (homozygous) and Mtbp+/- (heterozygous) mice. Mtbp heterozygous mice had increased longevity compared to wild-type controls, exhibiting a median survival of 785 days compared to 654 days, a 20% increase. This significant difference in lifespan was represented in both male and female populations. Mtbp heterozygous males had a median survival of 774 days, compared to 672 days for wild-type control males, a 15.2% increase. Mtbp+/- females had a median survival of 790 days, compared to 650.5 days for Mtbp+/+ females, a 21.4% increase. In addition to median lifespan, Mtbp heterozygosity also increased maximum lifespan. Specifically, Mtbp+/- mice were overrepresented in the longest living decile and quartile of mice with 9 of 11 (81.8%) and 19 of 26 (73.1%) of the mice, respectively. In contrast, Mtbp wild-type mice were disproportionally represented in the shortest lived decile and quartile of mice 90.9% and 80.8%, respectively.
As is commonly seen in C56BL/6 mice, gross and histopathological tissue analysis at time of death of representative mice demonstrated the majority had cancer (17 of 23 Mtbp+/+ mice and 29 of 34 Mtbp+/- mice). Notably, 32.4% of Mtbp+/- mice had lymphoma, which was twice the incidence of lymphoma in Mtbp+/+ mice (17.4%). The lymphomas were detected at an average age of 840 days in heterozygotes, compared to 682.3 days in wild-type controls, a significant delay. Similarly, Mtbp+/- mice developed carcinomas later in life at 848 days (8.8%) compared to 694 days for Mtbp+/+ mice (13.0%). Although twice the proportion of Mtbp wild-type control mice were cancer free at time of death (30.4%) compared to Mtbp heterozygous mice (14.7%), the Mtbp+/- cancer-free mice lived an average of 836.4 days compared to 640.3 days for cancer-free wild-type controls. This difference in Mtbp+/- mice represents a significant delay in mortality among cancer free mice. These data collectively indicate a decrease in Mtbp expression alters the tumor spectrum and age of onset as mice age, as well as extends overall survival independent of cancer development.
Long-lived mouse models will often retain elevated motor function compared to controls, particularly as they age. To determine if Mtbp heterozygosity improved locomotor activity, open field testing was performed for 1 hour on two days with a cohort of old (1.5 year) littermate matched mice. Although there was a trend for Mtbp heterozygotes to travel a greater distance (5737.7 cm) compared to wild-type controls (4551.0 cm), this difference did not reach statistical significance. When locomotor function was actively challenged using a rota-rod endurance test, the Mtbp+/- mice (78.0 seconds) performed similarly to Mtbp+/+ mice (73.6 seconds) after training. In nature, many animal species with increased longevity have reduced reproductive capacity to limit overpopulation. This trend has been reported in some long-lived mouse models. Thus, we compared the reproductive efficiency of Mtbp+/+ and Mtbp+/- female mice. This examination did not reveal a significant difference in the average number of pups per litter birthed by Mtbp+/+ and Mtbp+/- females. Some long-lived mouse models reported to have reduced growth, resulting in smaller body size. We detected no size differences in mature Mtbp+/- mice. Given this observation, it was not surprising that analysis of serum isolated and frozen at time of sacrifice did not show a statistically significant difference in the level of circulating insulin-like growth factor-1, a major growth-promoting factor.
In addition to increased longevity and modulated cancer development, long-lived Mtbp heterozygous mice exhibited a global trend toward elevated cellular metabolism in the liver. Collectively, increased expression of metabolic markers suggests retained vitality in the livers of old Mtbp+/- mice, which coincides with the elevated expression of the well-known anti-aging gene Sirt1. Collectively, the data suggest Mtbp impacts longevity and cellular metabolism, particularly in the liver. These results are in line with a recent report on Myc as well as our previous reports indicating Mtbp is a positive regulator of Myc transcriptional activity. However, the effect of Myc heterozygosity appears broader than the effects observed for Mtbp heterozygosity. The precise reason for these differences is unclear at this time. Part of the downstream effects of Myc are mediated through direct binding to or displacement of other factors. It is unknown how Mtbp expression impacts these functions of Myc or whether these functions of Myc change as animals age. Moreover, it is possible Mtbp may only orchestrate a sub-set of Myc's overall transcriptional activity and may have Myc-independent functions. Therefore, additional research is needed on the interaction between Mtbp and Myc, and Mtbp itself, to better understand the contribution of Mtbp to aging.
I agree But don't forget that sometime in the future, even if it's still decades away, this Knowledge will be of great use, and possibly even crucial for escape velocity to be really achieved at some Point. The problem Is you dont know how efficient Sens therapy, especially the first rounds, will be. So its very important that people have already started gathering data on the complicated process which I'm sure could help find weak points in the current understanding of damage repair. For example, regarding mitosens, it will be crucial to Understand what roles does fusion and fission play for damage repair, what is the exact role of transcomplentation between mitochondria and so. It will be important at some point. I would say that both research directions should be taken, and probably youre right in that more of the overall focus should be placed on repair, cuz without it, we wont succeed either.
Huh? What must not be forgotten is that this is part of the mechanism of calorie restriction and thus its benefits for human lifespan, if any, will be (a) quite small, like CR is, (b) smaller and smaller as you become older, since it only slows damage accumulation instead of clearing it, and (c) accompanied by very complex side-effects.
K said: "For example, regarding mitosens, it will be crucial to Understand what roles does fusion and fission play for damage repair, what is the exact role of transcomplentation between mitochondria and so."
Fusion and fission are irrelevant for mitosens, since what mitosens modifies is not mitochondria but the cell nucleus.
@Antonio - I think K is implying that there may be some kind of hidden accumulating damage hidden in the process of mitochondrial fission and fusion independent of mtDNA gene deletions that isn't apparent at present.
Mitochondria readily move from one cell to another, especially to cells in distress.
Just provide a batch of stem cells with good mitochondria and the problem should go away on it's own.
No need to think how to over-complicate before we've tried the simple solution.
@Anonymoose: That's no solution. Mutant defective mitochondria are widespread in old age because they have a selective advantage.
It works for fibrosis.
You're not keeping up with stem cell research.
Could you be more specific?
I agree that repair is the way to go, but the easiest way to get replacement parts is to use the way nature has perfected for billions of years, grow organs.
First step is to build an artificial womb. Something that could have been achieved decades ago, if it would have been researched. In 2003, scientist succeeded in growing a mouse embryo almost to full term, but the research is controversial so scientists and universities don't want to work in the area. Imagine if this was not the case and if the research got proper funding.
Once we have full control of the process, we can build specific body parts, like hearts and livers. Perhaps a whole body could be built. We can't replace the human brain, so the technology will not be the final answer, but it could probably buy us 30 more years. I expect the brain to get some rejuvenation too, if the body consists of young cells.
@Erik: Search for ectogenesis for more info on artificial wombs. My point is as you write there are too little R&D on it based on the reasons you wrote. I mailed XPrize few years ago asking them to set up a prize. If I were a millionaire I would set up the prize alone. I think that if people interested in biotech (BT) could come together, we could made a proposal and fund the prize.
@Erik: Something new in Assisted Reproductive Technologies as ectogenesis might derive from the EU program reprounion:
http://reprounion.eu