Lecture 2: How to find a cure for ageing, part 2
David Gems - Biology 338, February 2005 DrosophilaWe have established that mammals have homologues of the genes which control lifespan in C. elegans. But what is the likelihood that these genes actually control lifespan in mammals? It remains possible that the role of insulin/IGF signalling in ageing in C. elegansis just some bizarre effect linked to the fact that C. elegans make dauer larvae. One way to address this is to ask: Do mutations in the equivalent genes extend lifespan in a completely different short-lived animal species, one that does not have dauer larvae. A convenient species with which to test this is Drosophila. OH: Fly mutants During the last few years this approach was taken by Linda Partridge and myself here at UCL, and in the laboratory of Mark Tatar and Brown University. We examined mutants affected in a number of genes in the insulin/IGF-1 signalling pathway. Mutations in two of these genes proved to have strong effects on ageing: These were chico, homologous to insulin receptor substrate, and INR, homologous to the DAF-2 insulin/IGF receptor. [Medline entry]. [Medline entry]. These results show that insulin/IGF signalling has an evolutionarily conserved role in the modulation of ageing. The first long-lived Drosophila mutant was reported by Seymour Benzer's lab at the California Institute of technology in 1988. The gene was called methuselah (Mth) [Medline entry]. Its life span is increased by ~35%, and animals are stress resistant. In this respect they resemble C. elegans daf-2 and age-1 mutants. More recently, a second lifespan gene, named I'm not dead yet (Indy) has been identified. [Medline entry]. Insulin/IGF-1 signalling and ageing in mammals Mice Insulin/IGF signalling modulates ageing in nematodes and insects. Is it possible that homologous pathways control ageing in mammals? OH: IIS in mammals While in worms and flies there is a single insulin/IGF receptor, in mammals there are at least 3. These are: The insulin receptor, the IGF-1 receptor, and a third receptor of unknown function, known, rather ponderously, as the insulin receptor-like receptor. Which receptor might regulate ageing? It has been suggested that since insulin is involved in responses to nutrition and CR extends lifespan, that the effects of CR on lifespan may be mediated by insulin. But there are problems with this idea. Mutations in the mammalian insulin receptor do not extend life span - in fact they result in non-insulin dependent diabetes, which shortens life span. OH: Leprechaunism This poor little fellow has leprechaunism, which results from a severe loss of function mutation in the insulin receptor gene. Leprechaunism is associated with low birth weight, hyperinsulinemia, low birth weight, and failure to thrive. In mice, targeted knockout of the insulin receptor gene results in neonatal lethality. This, it does not seem likely that insulin signalling accelerates ageing. On the other hand, if you completely knock out the insulin/IGF receptor gene in worms or flies, the resulting mutation is lethal. Possibly if you reduced insulin signalling by just the right amount you would see a retardation of ageing. In fact, last year there was a report that provided some support for this idea. Tissue specific deletion of IR [using Cre recombinase/loxP recombination site system] in the white adipose tissue of the mouse increases lifespan - though not a very large effect. FIRKO mouse. Suggests adipose tissue may be a key regulator of ageing. [Medline entry] OH: What about the IGF-1 receptor? Let me remind you first what IGF-1 is. IGF-1 is a cell growth and survival factor. Production of IGF-1 is regulated by growth hormone from the anterior pituitary gland. In fact, almost all that GH does is to promote IGF-1 production. So IGF-1 controls body size. If you lack GH, you are a dwarf. During recent years a lot of indirect evidence has accumulated for a role of IGF-1 in ageing. Several dwarf mice with defects in GH production or sensitivity, such as the Ames and Snell dwarves, show large increases in lifespan. [Medline entry][Medline entry][Medline entry] Last year it was also shown that loss of a single copy of the IGF-1 receptor can increase lifespan in mice. [Medline entry] Thus, experiments inspired by the genetics of ageing in C. elegans suggest that both insulin and IGF-1 signalling control the rate of murine ageing. There is currently a collaborative project based here at UCL to continue to unravel the parallels between the genetic control of ageing in C. elegans, Drosophila and mice. IIS and human ageing Does insulin and/or IGF-1 signalling control the rate of human ageing? A small minority of individuals outlive the rest of us... centenarians and supercentenarians: Are these people with reduced insulin/IGF signalling? Was Jeanne Calment, who lived to the age of 122, a long-lived mutant? How can this be tested? 1) By testing for allele-specific demographic selection at candidate loci This has been attempted in a recent study, where changes with age in allelic variants were tested for the genes IGF-1R (the IGF-1 receptor, cf. C. elegans DAF-2), PI 3-kinase CB (cf C. elegans AGE-1), IRS-1 (c.f. Drosophila chico), and FOXO1A (cf. C. elegans DAF-16). One variant of IGF-1R gene was over-represented among long-lived people, and associated with reduced levels of circulating IGF-1. The effects of this polymorphism was enhanced by one variant of the PI3KCB gene. [Medline entry] 2) Association studies using centenarian sibships. 308 individuals, of 137 sibships were examined. Linkage of a locus on chromosome 4 (D4S1564) to longevity was identified. [Medline entry] Ethics of research into ageing Finally, I'd like to ask the question: do we want to seek treatment for ageing? Or if you like: what is the ultimate goal of biogerontology (Table) Here's a rather old table of the major causes of death in the USA. The two major causes of death in the developed world are cardiovascular disease - especially heart disease and stroke - and cancer. A great deal of research funding around the world is invested into seeking treatments for these diseases. Yet the principal risk factor for these diseases is age. As Ronald DePinho put it in a recent review in Nature, "Advancing age is the most potent of all carcinogens". [Medline entry]. Any treatment that prevented or slowed the underlying ageing process even to the slightest degree would have an enormous impact on a wide spectrum of diseases. As Robin Holliday pointed out: It makes more sense to seek treatments for ageing as the major risk factor for cancer, cardiovascular disease, diabetes, Alzheimer's disease and so on, than to aim to treat these diseases piecemeal. [Medline entry]. By analogy, seeking cures for heart disease alone is a little like taking a contaminated water supply and removing the cholera bacterium alone from it, rather than completely sterilising the supply. Thus, in ethical terms, it seems right to pursue treatments for ageing - it would be unethical not to pursue them. But of course, beyond disease prevention, treatments for ageing would have a further consequence: they could potentially increase lifespan. Work with model organisms have demonstrated that major extension of the lifespan of species is possible, as we have seen. It may be possible by manipulating insulin/IGF signalling to increase human lifespan by many decades. This is something that some people find worrying. Some of these worries are practical - overpopulation, equality of access to anti-ageing treatments, the possibility of extending the moribund phase of ones life. But beyond that are deeper concerns - about the impact of life extension on the fundamental nature of human existence, or human identity. Is there an optimal length to a human life - beyond which one would not want to go? These are issues that all of us need to think about. For a review of ethical implications of research on ageing, see [Medline entry] Download ethics paper in pdf format.
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