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Palsdottir A, Helgason A, Palsson S, Bjornsson HT, Bragason BT, Gretarsdottir S, Thorsteinsdottir U, Olafsson E, Stefansson K. A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries. PLoS Genet. 2008 Jun;4(6):e1000099. PubMed.
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University of Massachusetts Medical School
The Bjornsson et al. study provides further evidence that DNA methylation differences between individuals increase with age. However, the study not only confirms this principle, but shows that genetic factors play a role in inter-individual methylation differences. It highlights the complexities when studying DNA methylation in aging. While it is thought that "environmental" factors such as alcohol, diet, perhaps medications, etc., play a role in modifying DNA methylation patterns in the genome, genetic factors could play a role as well. Recently, we identified in a postmortem brain study 2/50 gene loci that showed significant alterations in Alzheimer's subjects, as compared to controls (Siegmund et al., 2007). Interestingly, the changes in the Alzheimer's cohort, in terms of DNA methylation, appeared to reflect an acceleration of normal aging. Therefore, one could assume that the findings of Bjornsson et al. will be of great interest for aging-related disorders, including Alzheimer disease.
References:
Siegmund KD, Connor CM, Campan M, Long TI, Weisenberger DJ, Biniszkiewicz D, Jaenisch R, Laird PW, Akbarian S. DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS One. 2007;2(9):e895. PubMed.
View all comments by Schahram AkbarianUniversity of Southern California
Palsdottir et al. show in a fascinating analysis a major decrease in the age of death in carriers of hereditary cystatin C cerebral angiopathy (a L68Q mutation in the cystatin C gene) since the eighteenth century. The comparison with spouse lifespan is particularly striking because life expectancy of those surviving to adults was increasing at the same time as life expectancy of the L68Q carriers (“age of lethality penetrance”) was decreasing. In considering the possible environmental factors during these 200 years, the authors note the striking shift in diet composition, including a twofold greater carbohydrate intake (Fig. 7). It is also likely that the total caloric intake increased since the 1800s. Iceland suffered a major food shortage after the Viking age due to the increasingly cold climate: the population declined by about 35 percent and adult height shrank by two inches. As Einarsson (1573-1659) described it: "Formerly the earth produced all sorts of fruit, plants and roots. But now almost nothing grows.... Frost and cold torment people. The good years are rare.” The eighteenth century Icelanders were plausibly still under severe caloric restriction, compounded by micronutrient deficiency. Even in the later nineteenth century with improving climate, Iceland was one of the poorest countries in Europe.
If this view is valid, then we may consider that caloric restriction was protective for cystatin C L68Q penetrance at an early age. In fact, caloric restriction is protective in various mouse models of brain amyloidosis, familial dominant Alzheimer mutant genes, and of aortic atherosclerosis (Finch, 2007, Chapter 3.2.2; Patel et al. 2005; Wang et al. 2005). There is thus good rationale to examine cystatin C L68Q and other angiopathic mutations for responses to caloric restriction in mouse models as a new approach to prevention.
See also:
Einarsson O, quoted in Decline of the Vikings in Iceland.
Finch CE. 2007. The Biology of Human Longevity. Inflammation, Nutrition, and Aging in the Evolution of Lifespans. Academic Press: San Diego.
References:
Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, Morgan DG, Morgan TE, Finch CE. Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging. 2005 Jul;26(7):995-1000. PubMed.
Wang J, Ho L, Qin W, Rocher AB, Seror I, Humala N, Maniar K, Dolios G, Wang R, Hof PR, Pasinetti GM. Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB J. 2005 Apr;19(6):659-61. PubMed.
Palsdottir et al. conducted extensive linkage disequilibrium and genealogical studies of patients with HCCAA (also called hereditary cerebral hemorrhage with amyloidosis, Icelandic type—HCHWA-I) and found a decrease in age at onset of the disease, and age at death, of mutation carriers during the nineteenth century. This decrease in age at death, from 65 years in carriers born in 1825 to the present-day average of about 30 years, occurred while an increase in lifespan was documented in the general population in Iceland. This decrease in lifespan paralleled a major change in diet, most significantly an increase in sugar and salt intake in Iceland.
This study has important significance for our understanding of factors that affect amyloid deposition as well as cerebral hemorrhages. Studies, mainly in animal models of amyloidosis, should be conducted to determine the role of carbohydrates and/or salt in either cerebral amyloid angiopathy (CAA) or cerebral hemorrhage. Carbohydrates have been related to both. Multiple studies have suggested a link between type 2 diabetes and stroke and that glucose lowering in high-risk patients would lower the risk of the disease. In addition, type 2 diabetes mellitus has been associated with a higher incidence of Alzheimer disease (AD). Excess consumption of sugar-sweetened beverages plays an important role in the epidemic of obesity, a major risk factor for type 2 diabetes mellitus. A study has shown that APP/PS1 transgenic mice that were provided with 10 percent sucrose-sweetened water had exacerbation of memory impairment and an increase in insoluble Aβ levels and deposition in the brain compared with control mice with no sucrose added to the water.
The Leu68Gln variant of cystatin C forms amyloid deposition in cerebral and spinal arteries and arterioles, leading to recurrent hemorrhagic strokes causing serious brain damage and eventually fatal stroke. In vessels affected by CAA, local muscle and elastic elements are lost and replaced by amyloid fibrils, thereby weakening the overall structure of the vessel. Consequently, it was suggested that CAA predisposes towards cerebral infarction and cerebral hemorrhage. However, CAA is usually asymptomatic and only a subpopulation is at high risk of hemorrhage. Several studies implicated non-fibrillar cystatin C in amyloid β-CAA-related hemorrhage. Therefore, it would be of great interest to study whether a change in carbohydrate consumption affects amyloid deposition and/or the occurrence of cerebral hemorrhages with significance not only for cystatin C-related cerebral amyloidosis, but also for AD and stroke.
Alzheimer Support Group
These are indeed highly interesting papers.
To add to the story of epigenetic influences in the aging process, a new and fascinating study was published in PLoS ONE. The group around Axel Schumacher et al. at the Technical University Munich/Germany could show that people with late-onset Alzheimer disease have indeed an increased “epigenetic drift” in genes that may be responsible for some of the observed phenotypes. Additionally, the group found that some genes that participate in amyloid-β processing and methylation homeostasis show a significant interindividual epigenetic variability, which may contribute to disease predisposition. The observed epigenetic pattern would complement and support the aforementioned data, showing that the changes in the Alzheimer brain appeared to reflect an acceleration of normal aging. This could indicate that everybody has a certain likelihood of developing the disease.
References:
Wang SC, Oelze B, Schumacher A. Age-specific epigenetic drift in late-onset Alzheimer's disease. PLoS One. 2008;3(7):e2698. PubMed.
View all comments by Jutta BremerMake a Comment
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