Press Release
Discovery of a new long-lived mouse increases prospects of drugs to treat ageing
Date: October 2nd 2009
A new study by researchers at the Institute of Healthy Ageing published today in the journal Science describes a new long-lived mouse mutant whose characteristics provide a potential route to future treatments for ageing. The study was carried out by a consortium of research teams lead by Professor Dominic Withers.
The study shows that inactivation of a gene called S6K1 in mice leads to increased lifespan and improved health in later life. S6K1 is part of a system that responds to changing levels of food in the body, leading to changes in growth, reproduction and, it now transpires, ageing.
The effect on lifespan was seen only in females, for reasons that remain unclear. The female knockout mice were leaner throughout life, and retained stronger bones; they performed better at motor performance tasks, a measure of attributes such as balance, strength and coordination, and were more inquisitive and exploratory, suggesting that their senses and cognition were better; they did not show the usual age decline in insulin sensitivity (which leads on to type II diabetes). Even their T-cells, an important part of the immune system, appeared more 'youthful', implying slowing of the usual age decline in immunity.
Nutrient sensing systems were previously shown to control ageing in short-lived invertebrate species such as the nematode C. elegans. S6K (ribosomal S6 kinase) is controlled by a second enzyme called Tor (target of rapamycin) in one particular nutrient-sensing pathway. The Tor/S6K pathway was shown in short-lived animals to mediate the effects of caloric restriction on lifespan. It was first discovered in the 1930s that caloric restriction (controlled reduction of food intake) can increase lifespan substantially in rodents. Caloric restriction also results in an extension of the youthful period of the lifespan, and protection against a wide range of ageing-related illnesses, including cancer. The mechanisms underlying the effects of caloric restriction have remained unclear.
Interestingly, S6K1 mutant mice resemble calorically restricted mice, e.g. in terms of their patterns of gene activity. This suggests that the Tor/S6K pathway mediates the effects of caloric restriction in mice as it does in invertebrates, and that the S6K1 mutation has recapitulated the caloric restriction programme that slows ageing.
The team also explored the mechanisms by which
mutation of S6K1 might increase
longevity. One clue was that these mice show increased activity of an enzyme
called AMPK (AMP-dependent kinase). This plays an important role in regulating
energy levels within cells, and is also known to promote longevity in
invertebrates. To test the possibility that S6K controls ageing via effects on
AMPK, the researchers used the nematode C. elegans.
Work by Dr Jennifer Tullet in the laboratory of Dr
David Gems at the IHA showed that the increased longevity of worm S6K
mutants
was dependent upon an increase in AMPK activity. The study also shows
that the S6K1 mice resemble mice that have been treated with AMPK
activating drugs.
"The possibility that AMPK activation slows ageing
is very exciting since AMPK can be activated using existing drugs" says David Gems. "In fact, a
group in Russia already has evidence that AMPK-activating drugs can slow ageing
in mice."
The S6K1 mouse study is the third of a trio of recent studies that bring scientists substantially closer to treatments that could slow the ageing process. One study, from the US, showed that caloric restriction can slow ageing in rhesus monkeys. This is important because it increases the likelihood that caloric restriction affects human ageing. Another study, also from the US, showed that inhibiting the pathway in which S6K1 functions using the drug rapamycin increases lifespan in mice. Rapamycin inhibits mTOR and its downstream signals, including S6K1. Taken together, these three studies increase the likelihood human ageing might one day be slowed by drugs that target the nutrient sensing pathways that mediate the effects of caloric restriction.
"What we have here is a druggable pathway with
striking effects on ageing," says
Withers. "If this could be targeted in people, it could produce
a reduction of age-related diseases across the board."
"Testing the effects of S6K on ageing was quite an undertaking," says Dr Colin Selman, who did much of the laboratory work. "The
lifespan measurements alone took four years, but in the end it was well
worth it. This mouse has taught us a great deal about ageing." Selman recently set up his own ageing research laboratory at the University of Aberdeen.
"The S6K findings really show how work on creatures like nematodes and fruitflies can lead to fundamental discoveries about ageing in mammals" says David Gems. "The time now seems ripe to start testing for benefits of using specific drugs that target this pathway in humans."
Much of the work in this study was conducted at the Institute of Healthy Ageing (IHA) at UCL. The IHA was created in 2007 as a centre of excellence for research on the biology of ageing, and to promote the translation of findings from research biogerontology into therapies to improve the health of older people. The S6K1 mouse study fulfils both facets of the IHA remit.
Further information
1. Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life-span. Science; 2 Oct 2009.
2. Media release from the Wellcome Trust - see here
3. Institute of Healthy Ageing - The IHA (Director: Prof. Dame Linda Partridge) opened in 2007 as a centre of excellent for research on the biology of ageing. The remit of the IHA is as follows.
The biological process of ageing contributes to increased risk of a wide range of diseases, from neurodegenerative diseases (e.g. Alzheimer's and Parkinson's disease) and cancer to cardiovascular disease (causing heart attack and stroke) and age-related macular degeneration (causing blindness in the elderly). Our primary purpose is to bring together researchers working on the basic biology of ageing (biogerontology) with those working to understand the causes of ageing-related disease. By merging biogerontology and the study of ageing-related diseases, we aim to develop a new translational biogerontology using the ageing process as a point of intervention to protect against the diseases of old age. Our goal is to improve the health and quality of life for older people.
The work of the Institute of Healthy Ageing is pursuing these ends by (1) conducting world class research on the biology of ageing and ageing-related disease; (2) increasing capacity in research on the biology of ageing by training new researchers and nurturing the work of younger principal investigators; (3) teaching about the biology of ageing at undergraduate and postgraduate levels.
We aim, through our combined activities, to transform healthcare technology and the social conditions of the elderly to create a future society in which the lives of older people are healthy, meaningful and happy.
4. UCL (University College London) – Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. UCL is the seventh-ranked university in the 2008 THES-QS World University Rankings, and the third-ranked UK university in the 2008 league table of the top 500 world universities produced by the Shanghai Jiao Tong University. UCL alumni include Marie Stopes, Jonathan Dimbleby, Lord Woolf, Alexander Graham Bell, and members of the band Coldplay. UCL currently has over 12,000 undergraduate and 8,000 postgraduate students. Its annual income is over £600 million. http://www.ucl.ac.uk
5. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. http://www.wellcome.ac.uk
6. Further information on Dominic Withers, Colin Selman, David Gems, Linda Partridge.
7. Images. The
following image is freely available for duplication
Dr. Colin Selman.
