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.
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.
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.
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.
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.
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.