Gerontology and Geriatrics 1

Pathophysiology, epidemiology and therapy of ageing

Principal Investigators

Prof. Dr. R.G.J. Westendorp, Dr. G.J. Blauw, Dr. A.J.M. de Craen, Dr. Ir. E.W. van Heemst 

Aim and focus

Each species has its own characteristic lifespan. However, spans vary widely within a species individual life. To a great extent this variability in lifespan is the result of the individual ability to avoid or cope with internal and external damage. The aim of our work is to identify the biological mechanisms that determine the presence and absence of disease in old age contributing to the variation in individual lifespan. To this end we use evolutionary conserved pathways and test these in human populations. For example, single point mutations in the insulin-signaling pathway of C. elegans can lower the rate of aging and increase lifespan by up to nearly five times as long as the wild type worms. This suggests that a major part of the age-related changes are under coordinated genetic control.

Position in international context

Within the field of aging research there has always been a clear distinction between groups studying model organisms and cells (traditional gerontology) and those who tackle clinical problems of old people (traditional geriatrics). Places of interaction between these two fields have rarely been successful and have generally resulted in a lack of focus. Our group is becoming increasingly renowned as one of the very few centres in the world that is succesfully combining these two fields (see: Chen I. Tying it together. Sci Aging Knowl Environ 2004 (9), nf23).

Content/highlights/achievements

We have found convincing arguments that trade offs exist in the regulation of human life histories that determine the occurence or absence of numerous diseases in middle and old age. We were the first to demonstrate that variation in the insulin-signaling pathway and TP53 is associated with human lifespan (Leiden 85-plus studies). Moreover, we have shown that risk factors of disease at middle age cannot always be extrapolated to old age. Amongst others, we have demonstrated that high levels of total cholesterol do not have detrimental effects whereas low thyroid function appears to be beneficial. We have also performed an unprecedented large randomized controlled trial in elderly people (PROspective Study of Pravastatin in the Elderly at Risk, PROSPER) to test whether cholesterol lowering has any clinical benefit.

Future themes

We have finalized the recruitment of one the world biggest, but clearly the most extended series of 500 families that are genetically enriched for genes encoding longevity (The Leiden Longevity Study). This sample, for which we have sophisticated phenotypes and bio-materials will provide us with a unique instrument to apply genomic-, proteomic-, and metabolomic-platforms to further unravel the biomolecular pathways of the ageing process.
We have recruited a unique population based sample of 1500 newborns, 500 very old age and 2000 women with fertility histories from the remote area of Bawku Upper East Ghana (Africa Longevity study). All subjects, for whom we have DNA available, are included for annual follow-up visits to determine fertility and mortality rates. Furthermore, we are coordinators of the FP6-funded Network of Excellence “LifeSpan” ( http://www.lifespannetwork.nl) that integrates research into development and ageing. The overall aim of the network is to establish the relationship between early-life events, and late-life survival, and health and to identify the mechanisms that underpin this relationship. In LifeSpan we move between observations in humans and experiments in (in)vertebrate models, to test effects detected in one species in the context of candidate longevity mechanisms in the others. All activities are aimed at obtaining a better understanding of the development and aging process of humans in their 'natural' environment (see: Abbott A. Aging gracefully. Nature 2004; 428: 116-118).

Cohesion within the LUMC

We collaborate closely with the departments of Neurology, Psychiatry, Radiology and Cardiology within the research foci 'Neurodegenerative Diseases' and ‘Vascular Medicine’. We also work closely with the section of Molecular Epidemiology and the 'CMSB initiative' making use of the high throughput genetic platforms. We also cooperate closely, amongst others, with the Department of Clinical Chemistry, Parasitology to perform high throughput analyses of proteomic and metabolomic markers.

Key publications  1998-2007

Schram MT, Trompet S, Kamper AM, de Craen AJM, Hofman A, Euser SM, Breteler MMB, Westendorp RGJ. Serum calcium and cognitive function in old age. J Am Geriatr Soc 2007; 55:  1786-92.
IF 3.3

Van den Berg E, Biessels GJ, de Craen AJM, Gussekloo J, Westendorp RGJ. The metabolic syndrome is associated with decelerated cognitive decline in the oldest old. Neurology 2007, 69: 979-85.
IF 5.7

VH ten Dam, van den Heuvel D, de Craen AJM, Blauw GJ, Bollen ELEM, Westendorp RGJ, van Buchem MA. Decline in total cerebral blood flow is linked with increase of periventricular but not deep white matter hyperintensities. Radiology 2007; 243: 198-203.
IF 5.3

Sattar N, Murray HM, McConnachie A, Blauw GJ, Bollen ELEM, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Murphy MB, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RGJ, Shepherd J for the PROSPER Study Group. C-reactive protein and prediction of CHD and global vascular events in the prospective study of pravastatin in the elderly at risk (PROSPER). Circulation 2007; 115: 981-9.
IF 10.9

Maier AB, Le Cessie S, De Koning-Treurniet C, Blom J, Westendorp RG, Van Heemst D. Persistence of high replicative capacity in cultured fibroblasts from nonagenarians. Aging Cell 2007; 6: 27-33.
IF 6.3

Gussekloo J, van Exel E, De Craen AJM, Meinders AE, Frölich M, Westendorp RGJ. Thyroid status, performance and survival in old age. JAMA 2004; 292: 2591-2599.
IF 24.8

Shepherd J, Blauw GJ, Murphy MB, Bollen ELEM, Buckley B, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, MacFarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott D, Sweeney BJ, Twomey C, Westendorp RGJ on behalf of the PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): randomised controlled trial. Lancet 2002; 360: 1623-1630.
IF 21.7

Westendorp RGJ, van Dunne FM, Kirkwood TBL, Helmerhorst FM, Huizinga TWJ. Optimizing human fertility and survival. Nature Medicine 2001; 7: 873.
IF 31.2

Izaks GJ, Westendorp RGJ, Knook DL. The definition of anemia in old persons. JAMA 1999; 281: 1714-1717.
IF 24.8

Westendorp RGJ, Kirkwood TBJ. Human longevity at the cost of reproductive success. Nature 1998; 396: 743-746.
IF 32.2