Heart Disease and the Oldest Old

This is an interesting article from the Archives of Internal Medicine on heart disease and elderly people. They suggest the results are surprising as heart disease is a disease of age and when we get older it should increase in incidence. What they find is that while heart disease does increases in individuals from 65-69 it drops dramatically when in an age cohort that includes individuals 85 and older (~10 %). I actually don't find these results all that astonishing as there appears to be an important shift in what the medical community uses as traditional risk factors for heart disease as individual transitions from middle age into being elderly (whatever that means). This would appear to be mirrored in these data as well.

I enjoy articles like this because they make us confront a whole host of issues that are going to become important over the next two decades. As I've mentioned before the fastest growing non-immigrant segment of US is those 85 and older (referred to as the oldest old). The problem is we really don't understand the underlying physiology of this transition and its implications for social policy and public health.

Incidence and Prevalence of Heart Failure in Elderly Persons, 1994-2003

Lesley H. Curtis, PhD; David J. Whellan, MD, MHS; Bradley G. Hammill, MS; Adrian F. Hernandez, MD, MHS; Kevin J. Anstrom, PhD; Alisa M. Shea, MPH; Kevin A. Schulman, MD

Background Recent analyses have presented conflicting evidence regarding the incidence and prevalence of heart failure in the United States. We sought to estimate the annual incidence and prevalence of heart failure and associated survival in elderly persons from January 1, 1994, through December 31, 2003.

Methods We conducted a retrospective cohort study of 622 789 Medicare beneficiaries 65 years or older who were diagnosed as having heart failure between 1994 and 2003. The main outcome measures were incidence and prevalence of heart failure and survival following a heart failure diagnosis.

Results The incidence of heart failure declined from 32 per 1000 person-years in 1994 to 29 per 1000 person-years in 2003 (P < .01). Incidence declined most sharply among beneficiaries aged 80 to 84 years (from 57.5 to 48.4 per 1000 person-years, P < .01) and increased slightly among beneficiaries aged 65 to 69 years (from 17.5 to 19.3 per 1000 person-years, P < .01). Although risk-adjusted mortality declined slightly from 1994 to 2003, the prognosis for patients diagnosed as having heart failure remains poor. In 2002, risk-adjusted 1-year mortality was 27.5%, more than 3 times higher than for age- and sex-matched patients.

Conclusions Although the incidence of heart failure has declined somewhat during the past decade, modest survival gains have resulted in an increase in the number of patients living with heart failure. Identifying optimal strategies for the treatment and management of heart failure will become increasingly important as the size of the Medicare population grows.

When "Bad" Genes go "Good"

PLOS Computational Biology has an early release of intriguing article related to evolution and aging entitled Buffering Mechanisms in Aging. by Bergman et al. (2007). Abstract below. The basic gist of this article is that while in most cases genes related to chronic degenerative diseases will kill you. However, except in some cases of older individuals where these genes appear to have a buffering effect and that I have written about previously here as well as here .This article investigates longevity and diseases in a cohort of long lived Ashekanzi Jewish populations and finds that the genes associated with chronic diseases are found in an increased frequency in the longer lived individuals within this populations. They then apply this gem of a quote

"Evolutionary theory can be summarized as the study of how genetic variation within a population is translated into variation between populations in response to natural selection, i.e., differential reproduction over the course of many generations. Similar principles can be applied to the study of changes in the genetic makeup of populations in response to differential survival over the course of one, or two overlapping generations. Differential survival in response to mortality will therefore be reflected in the prevalence of genotypes underlying the process of aging and longevity." (Bergman et al. 2007).

Personally, I don't agree with the basis for this. The author's argument is that genes associated with "exceptional longevity" (over 95 years) are being selected for. I'm not sure if this is the case because all of the individuals that were studied would have been in their 50s and if female would have been past reproductive age, so if they already had surviving offspring how is this natural selection. They argue that the phenotype is "exceptional longevity", which is rare, that those without the "longevity genes" are "weeded out" (their term) due to chronic disease, and that these "longevity genes" are buffering this subpopulation from chronic disease. They argue only the latter half of natural selection and not the survival of offspring, which is the true measure of fitness. So unless some of these centenarians are popping Viagra and breeding like rabbits it unlikely that this is being caused by selection. It is more likely being buffered by culture and then possibly enhanced through drift. There are a number of neutrality test statistics that would have allowed them to test this and demonstrate its statistical significance.

The far more interesting portions of their article have to do with the hypothesis that genes associated with "exceptional longevity" are buffering against chronic disease. Figure 3 in the article shown below (I love open access) does a good example of showing this with the U-shaped distribution. The article also does a decent job of explaining some of the genotypes may be associated with this. This helps explains an interesting trend in epidemiology which demonstrated that a number of traits associated with heart disease seem to increase with chronic diseases such as congestive heart failure. As the age of the general population has increased a number of these have noted the increase of traits considered to be risk factors actually end up appearing to be beneficial in older populations. This article does a good job of demonstrating a genetic component to these finding.





Citation: Bergman A, Atzmon G, Ye K, MacCarthy T, Barzilai N (2007) Buffering Mechanisms in Aging: A Systems Approach Towards Uncovering the Genetic Component of Aging. doi:10.1371/journal.pcbi.0030170.eor

An unrealized potential to understand the genetic basis of aging in humans, is to consider the immense survival advantage of the rare individuals who live 100 years or more. The Longevity Gene Study was initiated in 1998 at the Albert Einstein College of Medicine to investigate longevity genes in a selected population: the �??oldest old�?? Ashkenazi Jews, 95 years of age and older, and their children. The study proved the principle that some of these subjects are endowed with longevity-promoting genotypes. Here we reason that some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows disease-related genes to accumulate. Thus, studies of genotypic frequencies among different age groups can elucidate the genetic determinants and pathways responsible for longevity. Borrowing from evolutionary theory, we present arguments regarding the differential survival via buffering mechanisms and their target age-related disease genes in searching for aging and longevity genes. Using over 1200 subjects between the 6^th and 11^th decade of life (at least 140 subjects in each group), we corroborate our hypotheses experimentally. We study 66 common allelic site polymorphism in 36 candidate genes on the basis of their phenotype. Among them we have identified a candidate buffering mechanism and its candidate age related disease gene target. Previously, the beneficial effect of an advantageous cholesteryl ester transfer protein (CETP-VV) genotype on lipoprotein particle size in association with decreased metabolic and cardiovascular diseases, as well as with better cognitive function, have been demonstrated. We report an additional advantageous effect of the CETP-VV (favorable) genotype in neutralizing the deleterious effects of the lipoprotein(a) (LPA) gene. Finally, using literature-based interaction discovery methods, we use the set of longevity genes, buffering genes, and their age-related target disease genes to construct the underlying sub-network of interacting genes that is expected to be responsible for longevity. Genome wide, high-throughput hypothesis-free analyses are currently being utilized to elucidate unknown genetic pathways in many model organisms, linking observed phenotypes to their underlying genetic mechanisms. The longevity phenotype and its genetic mechanisms, such as our buffering hypothesis, are similar; thus the experimental corroboration of our hypothesis provides a proof of concept for the utility of high-throughput methods for elucidating such mechanisms. It also provides a framework for developing strategies to prevent some age-related diseases by intervention at the appropriate level.

Future Article URL: http://dx.doi.org/10.1371/journal.pcbi.0030170

The Tao of Human Aging

In 1900 the average life span of humans was 47 years old and by 2000 this had increased to approximately 77 years old (Crews 2003). From an evolutionary standpoint this is a tremendous increase in a relatively short amount of time and the process and epidemiological consequences that accompany an aging population are poorly understood. While several animals models have been used to study the effects of aging they are a weak substitute for humans aging with their long periods of adolesence and post-reproductive life history stages as mentioned in a recent article in PLOS Genetics by Martin et al. (2007).

Genetic Determinants of Human Health Span and Life Span: Progress and New Opportunities

George M. Martin^*, Aviv Bergman, Nir Barzilai

We review three approaches to the genetic analysis of the biology and pathobiology of human aging. The first and so far the best-developed is the search for the biochemical genetic basis of varying susceptibilities to major geriatric disorders. These include a range of progeroid syndromes. Collectively, they tell us much about the genetics of health span. Given that the major risk factor for virtually all geriatric disorders is biological aging, they may also serve as markers for the study of intrinsic biological aging. The second approach seeks to identify allelic contributions to exceptionally long life spans. While linkage to a locus on Chromosome 4 has not been confirmed, association studies have revealed a number of significant polymorphisms that impact upon late-life diseases and life span. The third approach remains theoretical. It would require longitudinal studies of large numbers of middle-aged sib-pairs who are extremely discordant or concordant for their rates of decline in various physiological functions. We can conclude that there are great opportunities for research on the genetics of human aging, particularly given the huge fund of information on human biology and pathobiology, and the rapidly developing knowledge of the human genome.

While this article is an excellent review of currently genetic theories of aging it does little in its attempt to explain the evolutionary implications of aging in human populations. Several hypothesis such as the Grandmother Hypothesis have been developed in why humans have such a long life span. While no doubt individuals survived past reproductive age in the past they did not probably do so in large number. Certain Neanderthals lived too a ripe old age such as Shanidar 1 who was between 40-50 years old and certain chimps such as CHETA (who was in the Tarzan movies in the 30s) and is currently 75. However, these are probably the exception rather than the rule. Today the fastest growing non-immigrant segment of the US population are those individuals 85 and older (currently 4.3 million), or as the gerontologists have termed them the oldest old. This is clearly something never experienced before in the evolutionary history of humans. Whereas in the past a few individuals may have survived this far, today a great number of us will reach this age category. As Martin et al. state understanding the underlying genetic mechanisms that allow certain individuals to live longer than others and several of these may have underlying genetic influences. So why do people live longer and are there selective factors influencing the age increase can become an anthropological question as well as a medical and political one. With the baby-boomers about to retire and an impending A(ging) bomb about to detonate it is becoming increasingly important to bring an anthropological perspective to the study of the elderly.

References

Crews D. 2003. Human senescence: evolutionary and biocultural perspectives. Cambridge: University of Cambridge Press. 291 p.