Looking for a magic pill to help you ward off ageing? No problem. With just a few clicks of your mouse you can buy enough snake oil to last your newly extended lifetime, complete with a list of promises as extravagant as the price tag.
Today鈥檚 booming market for anti-ageing products is founded on little more than hype and hope, but things are set to change. In the past few years, at least 10 gene mutations have been identified that extend the lifespan of mice by up to 50 per cent. Encouragingly, these long-lived supermice are no sickly rodent geriatrics: they remain healthy and active long after their litter-mates have succumbed to the many diseases of old age. The major hurdle in the quest to achieve similar results in humans is understanding exactly how these genes and others like them influence longevity.
One key factor, in mice at least, seems to be the production of growth hormones in early life. In 1996, the first mutation found to extend life in mice was one engineered into the so-called Ames dwarf mouse. Ames mice were given a mutation on the Prop-1 gene that affects the endocrine system, leaving them with a deficiency of growth hormone, among other hormones. It turned out they live up to 50 per cent longer as a result.
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Five other mutations that reduce production of insulin-like growth factor (IGF-1) have since been found to have a similar effect on longevity in mice. Something similar appears to happen in dogs. Small breeds, which have low levels of IGF-1 in early life, can live up to twice as long as larger dogs and remain free of signs of age-related disease until later in life.
Small is youthful
Could this point to the elixir of youth in humans? Hard evidence is scarce, but some as yet unpublished research suggests a subgroup of centenarians has a variation in one IGF-1 gene. Another gene variant, known as the Laron mutation, which affects the receptors for growth hormone and so leads to dwarfism, has also been anecdotally linked to longevity. Many experts see growth hormones and their receptors as possible targets for future anti-ageing drugs. The big obstacle is likely to be finding ways to sidestep the serious problems associated with growth hormone deficiencies, such as dwarfism and infertility.
An alternative and perhaps more promising route to longevity lies in finding ways to increase the resistance of cells to stresses such as the damage caused by free radicals. Many supposed anti-ageing compounds sold on the internet claim to work by providing antioxidants to mop up damaging free radicals, which are produced by the cell鈥檚 mitochondria when they make the ATP that fuels the cell鈥檚 activities. Though there is no evidence that popping antioxidant pills can hold back the years, delivering antioxidant enzymes direct to the mitochondria might do the trick. Experiments in mice show that this seems to protect mitochondrial DNA from mutations, extending lifespan by 20 per cent (麻豆传媒, 14 January, p 42).
To protect nuclear DNA, several different approaches are looking promising. Hot off the press comes research indicating that an aberrant form of a protein called lamin A plays a key role in damaging the nucleus and its contents, leaving it looking wrinkled (Science, DOI: 10.1126/science.1127168). Researchers from the National Cancer Institute in Bethesda, Maryland, were able to turn the clock back in old cells by blocking the production of this protein. Now they want to find out whether drugs that do the same thing can slow down ageing in animals.
Nuclear DNA is particularly susceptible to damage during cell division, when it is rearranged. In 1997, Lenny Guarente and David Sinclair from Harvard Medical School in Boston reported that this damage can cause ageing in yeast. They have since found that yeast with an extra copy of a gene called SIR2, which helps prevent this genetic rearrangement, lived between 30 and 50 per cent longer. Convinced that he has found a 鈥渓ongevity gene鈥�, Sinclair is now studying the life-prolonging effects of the equivalent mammalian gene, SIRT1, in transgenic mice. With the mice still only 2 years old, it will be another couple of years before we know whether this approach works.
鈥淎t least 10 genetic mutations have been found that increase the lifespan of mice鈥�
Meanwhile in humans there are tantalising hints that yet another member of this family of genes, dubbed the sirtuins, is linked to longevity. In 2003 a study led by Giovanna De Benedictis at the University of Calabria in Arcavata di Rende, Italy, reported that centenarian men were more likely than the general population to have two copies of the SIR3 gene.
Stress in a bottle
Can we harness the rejuvenative power of sirtuins? Sinclair is hopeful. Under normal circumstances, sirtuins are activated when cells are stressed, but he has found a set of plant molecules that bind to the SIR2 protein in a way that mimics the effects of mild stress in cells, so increasing the activity of sirtuin genes. Feeding mice one of these compounds, called resveratrol, which is found in red wine, suppresses the growth of cancerous tumours. Resveratrol has also increased the lifespan of every organism it has been tested in so far: yeast, nematodes, flies and fish. Sinclair鈥檚 next step it to find out whether it has the same effect in mice.
Other researchers believe their best chance lies in a fuller understanding of the physiology of ageing. To that end, Richard Miller from the University of Michigan in Ann Arbor is studying cells from another strain of lab mice, called Snell dwarf mice, in the hope of finding out how they resist attack on many fronts, including free-radical damage, heat stress and DNA mutations. Meanwhile, the US National Institute of Aging is funding a long-term project to test the effects of a slew of compounds with potential to manipulate physiological pathways implicated in ageing. Results of the first five trials on mice are due later this year. Wannabe centenarians, watch this space.