Immortal coils

Herodotus, the ancient Greek historian, wrote of the fabled longevity of an ancient Ethiopian people. When asked how they reached their 120 years, the Ethiopians revealed a fountain where they washed. The violet scented water was said to be like oil, making skin glossy and sleek, and after years of use one was granted long life. This is one of the earliest accounts of the fountain of youth, but the associated quest for physical immortality is peppered throughout many mythologies and religions. It still reverberates today in the fight for survival against age-related diseases. The secret of everlasting life, however, is unlikely to be derived from the fountain of youth but instead, from the humble nematode worm Caenorhabditis elegans.

Most cells can only divide a finite number of times, and as they age their DNA deteriorates. The ageing process is not haphazard, but is instead highly regulated by fundamental cell processes, such as signalling pathways. If the specific genes involved can be identified then there is the possibility of eventually altering them. Professor David Harrison of The Jackson Laboratory explains that “although ageing is not a disease, it is the clock that times most diseases and disabilities. Retarding ageing is a most effective preventative medicine.”

C. elegans worms complete their life span in about two weeks. But, through selective breeding and genetic testing, researchers have identified gene mutations that alter the ageing process. One such gene is daf-2, which produces a hormone receptor. These are proteins which bind to hormones in response to external signals. In the case of the daf-2 protein, this signal is cellular nutrients. C. elegans mutants with reduced daf-2 activity often live twice as long as normal worms. This is because there is a cascade of signals, which causes other proteins and cell products to be produced. Some are involved in disease resistance or cell maintenance, but the cumulative effect of them all together makes the cell live longer. While worms with an eliminated daf-2 gene are forced to enter a lengthy but sexually immature larval stage, worms with reduced daf-2 activity become normal adults with extended life spans.

There are groups of people who do have longer life spans than the average human, such as the Ashkenazi Jewish and a cohort of Japanese people. Based on C. elegans studies, the gene mutations responsible for cohorts of these populations were found to be relatives of daf-2, which, in humans, is another nutrient receptor, this time insulin. And so, from C. elegans began studies on mammals aiming to get closer to human immortality.

Once genes have been identified it is theoretically possible to alter their function. In 2009, a paper published in Nature reported that the drug rapamycin extended the life span of mice when administered in food. Rapamycin inhibits the rapamycin protein kinase (mTOR) pathway, which ordinarily stimulates growth and prevents recycling of old cell products. Rapamycin shifts protein function towards the maintenance of tissues and cells instead.

Lead author Professor Miller explains that this paper was exciting because “it was the first to show convincing evidence, in multiple labs, that a drug could extend maximum lifespan in mice.” It also showed that rapamycin administered late in life, 20 months, could still lead to longevity.

However, in follow up research some mice experienced weight loss from the treatment. When asked about the dangers this could pose in human treatment, Professor Strong of the research team explained “the reduction in weight was very small. The effect in males was less than 10% of the control weight at all ages, and less than 6% in females and only at one time point.” He went on to point out that “in the first paper we published in Nature, there was no weight loss detected when rapamycin treatment was started at 20 months of age, the equivalent of 60 years in humans with regard to the amount of lifespan remaining.”

But Professor Miller still sounds a word of warning “We are very far from having enough information to say that rapamycin could, or should, be used to treat or prevent human diseases. Rapamycin is given to some patients to prevent rejection of kidney grafts and relatives of it are given to some patients to treat cancer.  Strong drugs like these often cause a wide range of side effects, and in particular, rapamycin may block some sorts of protective immunity.”

 

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