Recent Examples of Modestly Slowing Aging through Genetic Manipulation in Laboratory Species

It is no longer remarkable to modestly extend life via genetic manipulation in worms, flies, and smaller mammals. Many demonstrations pass by without comment, a score or more new approaches explored every year. Below you'll find links to five recently published papers, each a different approach in flies or worms that slows aging and extends longevity by a small amount.

At this point much of the goal of this research is mapping: everything in cellular biochemistry is intricately interconnected, and so while there are probably only a handful of core mechanisms that slow aging, there is a near unlimited set of ways to influence those mechanisms. This situation makes it hard to figure out the identity of many of these biochemical switches, and equally hard to figure out which of the known switches are more important to aging. The operation of cellular metabolism is enormously, fantastically complicated, and still only superficially cataloged. There is a big difference between having a parts list and having full blueprints of the engine, and currently the state of knowledge is somewhere between those two extremes.

Extending life in lower animals through genetic alterations is a tool that can add to the overall knowledge of metabolism and how aging progresses: how the forms of damage that cause aging produce a chain of cause and consequence leading to dysfunction and age-related disease. A great deal is known of this damage, and a great deal is known about age-related diseases, but the middle of the chain is a big empty space on the map. Researchers aim to fill that in, and thus provide a complete accounting of aging at the molecular level. This process is unlikely to lead to methods of meaningfully extending healthy life span in humans in the near term, however. Its output along the way is well demonstrated by sirtuin research, or the focus on metformin, or on drugs influencing the mTOR pathway: marginal therapies capable of only slightly slowing aging, if that. These are all ways of adjusting the operation of metabolism to slightly slow down the rate of damage accumulation. The best path to near-future therapies for aging, a path capable of producing rejuvenation and greatly extended healthy life spans, is instead to build methods of repairing the well-cataloged forms of damage. That should be far less expensive, the roadmap to therapies is far more established, and the benefits provided by those therapies should be far greater.

So which of these approaches to pour funds into? It should be no contest, yet repair remains a hard sell. The disruption of existing institutions of aging research to focus more on repair of the known forms of damage than on exploration of metabolism is an ongoing battle, and repair-based approaches are still a minority concern in the broader field of medicine. Again, the purpose and culture of science is to create knowledge, not outcomes, and perhaps there is the challenge in this particular situation.

Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan

Methionine restriction extends the lifespan of various model organisms. Limiting S-adenosyl-methionine (SAM) synthesis, the first metabolic reaction of dietary methionine, extends longevity in Caenorhabditis elegans but accelerates pathology in mammals. Here, we show that, as an alternative to inhibiting SAM synthesis, enhancement of SAM catabolism by glycine N-methyltransferase (Gnmt) extends the lifespan in Drosophila. Gnmt strongly buffers systemic SAM levels by producing sarcosine in either high-methionine or low-sams conditions. During ageing, systemic SAM levels in flies are increased. Gnmt is transcriptionally induced in a dFoxO-dependent manner; however, this is insufficient to suppress SAM elevation completely in old flies. Overexpression of gnmt suppresses this age-dependent SAM increase and extends longevity. Pro-longevity regimens, such as dietary restriction or reduced insulin signalling, attenuate the age-dependent SAM increase, and rely at least partially on Gnmt function to exert their lifespan-extending effect in Drosophila. Our study suggests that regulation of SAM levels by Gnmt is a key component of lifespan extension.

Bmk-1 regulates lifespan in Caenorhabditis elegans by activating hsp-16

The genetics of aging is typically concerned with lifespan determination that is associated with alterations in expression levels or mutations of particular genes. Previous reports in C. elegans have shown that the bmk-1 gene has important functions in chromosome segregation, and this has been confirmed with its mammalian homolog, KIF11. However, this gene has never been implicated in aging or lifespan regulation. Here we show that the bmk-1 gene is an important lifespan regulator in worms. We show that reducing bmk-1 expression using RNAi shortens worm lifespan by 32%, while over-expression of bmk-1 extends worm lifespan by 25%, and enhances heat-shock stress resistance. Moreover, bmk-1 over-expression increases the level of hsp-16 and decreases ced-3 in C. elegans. Genetic epistasis analysis reveals that hsp-16 is essential for the lifespan extension by bmk-1. These findings suggest that bmk-1 may act through enhanced hsp-16 function to protect cells from stress and inhibit the apoptosis pathway, thereby conferring worm longevity. Though it remains unclear whether this is a distinct function from chromosomal segregation, bmk-1 is a potential new target for extension of lifespan and enhancement of healthspan.

Inhibition of elongin C promotes longevity and protein homeostasis via HIF-1 in C. elegans

The transcription factor hypoxia-inducible factor 1 (HIF-1) is crucial for responses to low oxygen and promotes longevity in Caenorhabditis elegans. We previously performed a genomewide RNA interference screen and identified many genes that act as potential negative regulators of HIF-1. Here, we functionally characterized these genes and found several novel genes that affected lifespan. The worm ortholog of elongin C, elc-1, encodes a subunit of E3 ligase and transcription elongation factor. We found that knockdown of elc-1 prolonged lifespan and delayed paralysis caused by impaired protein homeostasis. We further showed that elc-1 RNA interference increased lifespan and protein homeostasis by upregulating HIF-1. The roles of elongin C and HIF-1 are well conserved in eukaryotes. Thus, our study may provide insights into the aging regulatory pathway consisting of elongin C and HIF-1 in complex metazoans.

Nmdmc overexpression extends Drosophila lifespan and reduces levels of mitochondrial reactive oxygen species

NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC) is a bifunctional enzyme involved in folate-dependent metabolism and highly expressed in rapidly proliferating cells. However, Nmdmc physiological roles remain unveiled. We found that ubiquitous Nmdmc overexpression enhanced Drosophila lifespan and stress resistance. Interestingly, Nmdmc overexpression in the fat body was sufficient to increase lifespan and tolerance against oxidative stress. In addition, these conditions coincided with significant decreases in the levels of mitochondrial ROS and Hsp22 as well as with a significant increase in the copy number of mitochondrial DNA. These results suggest that Nmdmc overexpression should be beneficial for mitochondrial homeostasis and increasing lifespan.

Heart-specific Rpd3 downregulation enhances cardiac function and longevity

Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan in Drosophila melanogaster. Once revealed that long-lived fruit flies exhibit limited cardiac decline, we investigated whether Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three different stressors (oxidation, starvation and heat), heart-specific Rpd3 downregulation significantly enhanced stress resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted in other tissues or when other long-lived flies were tested in the heart-specific manner. Interestingly, the expressions of anti-aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart-specific Rpd3 downregulation. Showing higher resistance to oxidative stress, the heart-specific Rpd3 downregulation concurrently exhibited improved cardiac functions, demonstrating an increased heart rate, decreased heart failure and accelerated heart recovery. Conversely, Rpd3 upregulation in cardiac tissue reduced systemic resistance against heat stress with decreased heart function, also specifying phosphorylated Rpd3 levels as a significant modulator. Continual downregulation of Rpd3 throughout aging increased lifespan, implicating that Rpd3 deacetylase in the heart plays a significant role in cardiac function and longevity to systemically modulate the fly's response to the environment.
Comments

You would think with the potential future healthcare costs for the diseases of aging that kill us (2050 and 1 trillion for Alzheimer's disease alone gets thrown around a lot), that people would get their asses in gear and start putting more money into the repair method. But I think that to many scientists the repair approach just isn't viewed as real science, since they wouldn't need to know every last thing about aging and the metabolism. Not to mention the stigma that used to come with discussing extending lifespan.

So instead, we get things such as the likely near useless metformin trial with the goal of slowing aging. And the people running that make sure to emphasize they aren't looking to extend life in any meaningful way too, just to compress the period of decline. I don't know if that's just a PR move on their part or not, but I have my doubts. I know the FDA has said they can see the value in a drug that increases survival and prevents or delays disease, aging included, so my hope for that trial is pretty much that the FDA thinks about aging in a different manner. I'm not expecting anything else meaningful to come out of that. I know most people around here don't seem too high on HLI or Calico, but I really hope they have other things up their sleeves instead of the simply slowing aging approach. Different approaches are likely going to be needed. With all the useless things big pharma pursues, you would think one of the companies would take a gamble on SENS, or their own rejuvenation tool kits.

Posted by: Ham at September 24th, 2015 6:31 PM

Hi all, I greatly agree.

Repairing, as the damage accumulates, is a better way and the true way to continously push back advanced age/aging (damage accrual). Rejuvenation is in itself a true form of repair back to original unaged/undamaged biologically immature youth state. Many studies have shown that in order for the cell to repair its damage, it needs to restabilize its genome network (genome, genes, etc, a recent study demonstrated by a mathematical model that aging is a genetic product/result, not of damage accrual, but of genome network instability that cannot restabilize and genetically activate the repair program (the cell Redox, antioxidant capacity and different repair pathways) in face of rising oxidative stress. What's more is that this genome instability/reduced fidelity in transcription blocks important activation of the most important chromosome DNA telomeric repeat elongation, crucial, to biorejuvenation. That is, activation of the immortal inducing enzyme Telomerase with its hTERT transcript (genome instability makes for poor transcription)
Telomerase is crucial because it rejuvenates back the cell to youth state by tall telomeric DNA filling and thus activation of the 'gene signature' phenotype in children (gene silencing of death-program). How so ? Because the cell Redox restabilizes genome stability (by reducing oxidative stress through the cell's glutathione cycle and redox homeostasis), and upon doing so - allows Telomerase access to telomeric DNA repeats, to elongate them, the telomeres on the chromosome which determine our biological age and genome stability. Shorten telomeres are unstable and create this unstable genome that activates this death gene signature preprogrammed program that we like to call aging. Studies on biorejuvenated stem cells to an immature youth state all point to a most crucial mechanism, telomeres elongation back up to 16 kbs and total reversion of any damage accrual. High Telomeres genetically reprogram the program back to youth gene program, they activate trillions of interlapping gene pathways that reset the clock to 0 and the genetic transcription starts anew as if the damage was retroprogrammed/erased from the code. A crack Hack code that erases 'damage' line if you will.

My father takes metformin and it helps to keep his type II diabetes in check, so far so good, it really helps to lower his glucose and glycated hemoglobin (HbA1c); because when he stopped taking his medication (metformin), his blood glucose rose back up and thus it did help to control his diabetes; he went back on metformin and it stabilized. Clearly, I agree with you all, metformin is not working miracles, it is therapeutic and helps to get back your normal healthy life as if with no diabetes (reduces glycoxydation overload from excess glucose and insulin resistance back to regular levels. Normal glycoxydation AGEs accumulation continues and contributes to the regular rate of biological aging). My dad's hair is greying and he aged much more in the last 2 years; while taking metformin daily at the same time since near 15 years. Metformin can lenghten healthy lifespan (allowing a 10, 15 or 20 years in the long run on average lifespan, especially for people with accelerated aging (by glycoxydation AGEs accrual) as in diabetes) but never increase maximum lifespan in humans. On metformin, aging continues, it is just slowed and the rate of aging/damage accrual curves on graphics show that it goes all the way up to regular death - before 122 years old.
So no way around it, it is a bandaid plaster to slow down bleeding, but it still continues and one day a bit later thanks to metformin, dead anyway, you're fully bled out; before hitting 122. Aging and damage accumulation continued its biologically preprogrammed path.

Posted by: CANanonymity at September 25th, 2015 6:30 PM

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