Researchers in the UK found that by manipulating the genes of laboratory mice they could mimic the effect of calorie restriction and extend the mammals’ lifespan by up to 20 per cent as well as reduce the number of age-related diseases they suffered. It is hoped the finding will help the development of drug treatments for age-related diseases.
The study which was primarily funded by the Wellcome Trust, was led by scientists from the Institute of Healthy Ageing at University College London (UCL) and is published in the 2 October issue of the journal Science.
Experiments with rats in the 1930s showed that as long as there was sufficient intake of vitamins, minerals and other nutritients, the animals lived longer and stayed healthier, and more recent studies have suggested this may also be true of primates. Other studies suggest calorie restriction benefits human health, but it is not clear whether the approach also extends lifespan in humans.
The UCL researchers blocked a key molecular pathway that mimicked the health benefits of reducing calorie intake.
In this study, Professor Dominic Withers from UCL’s Institute of Healthy Ageing and colleagues experimented with “knockout mice” (genetically engineered mice where one or more genes have been silenced or “knocked out”).
They found that mice that had a gene deletion that stopped them being able to produce the ribosomal S6 protein kinase 1 (S6K1) lived longer and had fewer age-related diseases, such as of bone, immune system and motor dysfunction, and they also experienced less loss of insulin sensitivity.
However, Withers and colleagues found that the health and longevity benefits of S6K1 deletion was much more dramatic in female than in male mice. The male mice showed little increase in lifespan but they did show some of the health benefits. The researchers couldn’t find the reason for the gender-dependent lifespan difference.
Withers told the press that blocking the action of the S6K1 protein in the female mice added “life to their years” as well as “years to their lives”.
“The mice lived longer and were leaner, more active and generally healthier than the control group,” said Withers.
Withers and colleagues compared the knockout mice with “normal” mice (ie not genetically engineered in any way) when they reached 600 days, the equivalent of middle age in humans.
The female knockout mice were leaner, had stronger bones and they did not show the usual age-related reduction in insulin sensitivity, which protected them from getting type 2 diabetes. They also outperformed the normal mice in motor tasks and did better in a range of other areas where the researchers were able to measure balance, strength and coordination.
The female knockout mice also appeared to be more inquisitive and exploratory, an indication that they had better sensory perception and cognitive skills.
When they examined the T-cells (part of the immune system) they found that those of female knockout mice appeared more “youthful”, showing less signs of age-related decline in immunity.
On average, the female knockout mice lived over 160 days longer than the normal mice, to about 950 days, which meant their lifespan increased on average by 20 per cent.
The male knockout mice were also leaner than their normal equivalents, and they also showed less insulin resistance and appeared to have healthier T-cells.
S6K1 is a known component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, which influences the body’s response to changes in levels of the food we eat. Such sensitivity to changes in nutrient level result in corresponding adjustments in systems that affect growth, reproduction and now it would seem, ageing as well.
The authors suggest their discovery shows that calorie restriction acts via this signalling pathway, since S6K1 deletion induced gene expression patterns similar to those seen in calorie restriction, or when a second molecule called AMPK (adenosine monophosphate activated protein kinase) is activated with drugs.
AMPK is like a “master fuel gauge” that regulates energy levels within cells and influences the control of the metabolic response to calorie restriction. It becomes active when cellular energy levels fall, as they do under calorie restriction conditions.
They concluded that:
“Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR [calorie restriction] and could provide broad protection against diseases of aging.”
Some drugs currently used to treat humans for type 2 diabetes are thought to work by activating AMPK, metformim for example is one of them, and recent studies in Russia also suggested that the drug extended the lifespan of mice.
A more recent study in Nature showed that another drug, rapamycin, which is used to suppress the immune system in humans, such as to prevent organ rejection following a transplant, also extended the lifespan of mice. This drug also blocks the S6K1 pathway, although it could not be used in its current form in humans as an anti-ageing drug.
It would seem that evidence is gathering, via these various studies, that there exists a genetic signalling pathway that controls the ageing process in mammals, and that this pathway is sensitive to drugs, some of which may already be in use, albeit for other purposes.
Co-author Dr David Gems, also of UCL’s Institute of Healthy Ageing said it seems that we are “suddenly much closer to treatments for ageing than we thought”.
“We have moved from initial findings in worm models to having ‘druggable’ targets in mice,” he added.
Gems said the next step should be to test drugs like metformin and see if they slow ageing in humans.
Sir Mark Walport, Director of the Wellcome Trust, said if we are lucky we will age, but we are not so lucky if ageing also brings with it chronic diseases like diabetes, heart disease and dementia.
“This study reveals a biological pathway that may prove key to understanding the relationship between ageing and chronic illness,” added Walport.
“Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span.”
Colin Selman, Jennifer M. A. Tullet, Daniela Wieser, Elaine Irvine, Steven J. Lingard, Agharul I. Choudhury, Marc Claret, Hind Al-Qassab, Danielle Carmignac, Faruk Ramadani, Angela Woods, Iain C. A. Robinson, Eugene Schuster, Rachel L. Batterham, Sara C. Kozma, George Thomas, David Carling, Klaus Okkenhaug, Janet M. Thornton, Linda Partridge, David Gems, and Dominic J. Withers
DOI: 10.1126/science.1177221
Source: Wellcome Trust.
Written by: Catharine Paddock, PhD