Throughout history, longevity and eternal life have been the ultimate goal of humanity. From the king of the ancient Chinese Qin dynasty to the European alchemists during the medieval age, countless people have devoted their lives to unveil the secrets of immortality.
Although none of such efforts have been proven to grant eternal life, nowadays, modern scientists succeeded to elongate the lifespan of simple organisms, such as worms and flies, by a considerable amount with meticulous manipulation of our genes. Among many of those studies, there have been three main methods that held their significance even in the human body.
Most notably, the Scripps Research team discovered that the disruption of enzymatic pathways by small molecules can affect the lifespan of an organism. The team used Caenorhabditis elegans, a type of a roundworm, to test their hypothesis.
According to Benjamin Cravatt, Gilula Chair of Chemical Biology at Scripps Research, C.elegans worms were used for their experiment due to their relatively short lifespans (typically lives only a few weeks). Cravatt’s research involved about 100 compounds that were known to inhibit serine hydrolases in mammals.
In his experiment, Cravatt used each of the 100 molecules to block the enzymatic pathway and observed their effects on the lifespan of the C.elegans. When the team treated the worms that were 1 day into adulthood with the inhibiting compounds, they found that some of the compounds extended the average lifespan of the worm by at least 15%, according to Alice Chen, a graduate student in the Cravatt lab.
Chen elaborated that among the compounds, a carbamate compound called JZL 184, even extended the lifespan by 45% when treated at the optimal dose. Through further analysis, the team concluded that JZL 184 extended the worms’ lifespan by inhibiting fatty acid amide hydrolase 4(FAAH-4), which is known to break down a molecule called 2-AG, a molecule linked to aging in mammals.
What’s fascinating about this finding is that monoacylglycerol lipase was not present in C.elegans worms. MAGL usually breaks down the 2-AG molecules in mammals, but in the case of Chen’s experiment, FAAH-4 substituted the role of MAGL.
While the findings only apply to C.elegans worms as of now, the team stated that the FAAH-4 and 2-AG pathways will suggest a new path in extending human life.
In addition, a research team led by David Sinclair, assistant professor of pathology at HMS, found that calorie regulation extends the lifespan of yeast cells. According to Sinclair, the PNC1 protein regulates a vitamin called nicotinamide, which is an inhibitor of the Sir2 molecule. Sinclair further hypothesized that since Sir2 typically extends the lifespan of yeast cells by stabilizing the ribosomal DNA, the regulation of nicotinamide, which is its inhibitor, will consequently prolong the organism’s lifespan.
While the team believed that such a regulation process was initiated by the severe calorie restriction in yeast cells, they later discovered that calorie restriction had no impact on the Sir2 level. Thus, Sinclair’s team tested the effect of the molecule NAD on PNC1 levels to confirm that NAD was responsible for altering the Sir2 level. It turned out: NAD had no effect on the PNC1 level.
Undeterred, with more in-depth analysis, the team finally reached the conclusion that nicotinamide, which is one of the products of the reaction between Sir2 and NAD, was responsible for the change in Sir2 level. Based on the correlation they found between Sir2 level and nicotinamide facilitated by calorie restriction, Sinclair’s team is now investigating human genes that play the same role as PNC1, according to Harvard Medical School.
Finally, the research team led by John Tower, professor of biological sciences at the University of Southern California, found that the drug mifepristone extends the lives of female flies that have mated.
Before the experiment, Tower had set a premise that the sex peptide in female flies from male flies reduces the lifespan of the female flies as it causes inflammation. In his study, he and his colleagues discovered that the drug mifepristone, also called RU-486, blocked the effects of the sex peptide during reproduction, which retained the female flies’ health and thus extended their lifespan.
What played the most significant role in the reaction was, according to Tower, a molecule called the Juvenile hormone.
According to Tower’s research team, the juvenile hormone is responsible for the growth and development of fruit flies throughout their life. The sex peptide, they elaborated, boosts the effect of the juvenile hormone, which causes harmful inflammation in the flies’ body and enervates the male flies by shifting the metabolic pathways.
Therefore, the inhibition of the sex peptide by mifepristone also regulates the level of juvenile hormone, consequently extending the lifespan of the flies. With their further testing of the drug on C.elegans, which has similar genes as those of humans, Tower suggested that their findings may be applicable to extending the lives of humans.
The life-extending technology is still in its burgeoning stage, as it only applies to simple organisms, such as worms and flies. However, while eternal life still seems improbable, humanity will proceed one step further to unveiling the secrets of longevity with scientists’ perpetual efforts.