Life Expectancy in the US is unequal between regions

PLos Medicine has an interesting article on Life expectancy from birth in the US using mortality data at the county level. We all know that life expectancy has been increasing since 1960 (7yrs for men, 6 yrs for women) but what they find is that this is not always the case. If you look at the figure below you see that on average life expectancy increased from 1961-1983 nationwide but from 1983-1999 you see a steep decline (primarily in women) in the worst-off counties. The authors find that this result is due to halt in the reduction of cardiovascular disease, and a rise in lung cancer, COPD, and diabetes in both sexes along with an increase HIV/AIDS and homicide in men.

Counties are categorized into six groups on the basis of how their life expectancy changed in relation to national sex-specific change in life expectancy (4.1 y for men and 4.8 y for women in 1961–1983; 3.1 y for men and 1.3 y for women in 1983–1999). Actual life expectancies are shown in Figure S1, and absolute changes in life expectancy are shown in Figure S2.

Group 1, life expectancy increased at a level significantly higher than the national sex-specific mean; group 2, life expectancy increased at a level significantly higher than zero but not significantly distinguishable from the national sex-specific mean; group 3, life expectancy increased at a level significantly higher than zero but significantly less than the national sex-specific mean; group 4, life expectancy change was statistically indistinguishable from zero and from the national sex-specific mean; group 5, life expectancy change was statistically indistinguishable from zero and was significantly less than the national sex-specific mean; group 6, life expectancy had a statistically significant decline. All statistical significance was assessed at 90%.

P365R D20: The Poster (4/9/2008)

Today, I presented my poster at the Human Biology meetings. You can check out a copy of the poster here.

P365R D17: Aging in the US 2030 (4/6/2008)

I'm touching up a presentation for the Human Biology Association Meetings in Columbus and came across this slide that shows the estimates for the above 65 population in 2030 from the US Census Bureau. You can download the full presentation here (in MS PowerPoint) or the original data source from here.

Living to a 100

A couple of studies in the Archives of Internal Medicine investigate the oldest-old. The interesting aspect of this research that it seems that even individuals who have cardiovascular related morbidities have the ability to reach the century mark in some cases.

Disentangling the Roles of Disability and Morbidity in Survival to Exceptional Old Age

Dellara F. Terry, MD, MPH; Paola Sebastiani, PhD; Stacy L. Andersen, BS; Thomas T. Perls, MD, MPH

Arch Intern Med. 2008;168(3):277-283.

Background Although it is commonly held that survival to age 100 years entails markedly delaying or escaping age-related morbidities, nearly one-third of centenarians have age-related morbidities for 15 or more years. Yet, we have previously observed that many centenarians compress disability toward the end of their lives. Therefore, we hypothesize that for some centenarians, compression of disability rather than morbidity is a key feature for survival to old age.

Methods This cross-sectional, nationwide study included 523 women and 216 men 97 years or older. The participants were stratified by sex and age at onset (age <85> survivors] and age 85 years [termed delayers]) of chronic obstructive pulmonary disease, dementia, diabetes, heart disease, hypertension, osteoporosis, Parkinson disease, and stroke. Dependent variables were the Barthel Activities of Daily Living Index (Barthel Index) and the Information-Memory-Concentration test of the Blessed Dementia Scale.

Results Thirty-two percent of the participants were survivors. For men with hypertension and/or heart disease for 15 or more years, the median Barthel Index score was 90 (independence range, 80-100). For female survivors with hypertension, heart disease, and/or osteoporosis, the median Barthel Index score was 65 (minimal assistance range, 60-79). Generally, men had better function than women: 60% of male survivors had Barthel Index scores of 90 or higher compared with 18% of female survivors (P < .001) and 50% of male delayers had Barthel Index scores of 90 or higher compared with 27% of females delayers (P < .001).

Conclusions Whereas the compression of both morbidity and disability are essential features of survival to old age for some centenarians, for others, the compression of disability alone may be the key prerequisite. Though far fewer in number, male centenarians tend to have significantly better cognition and physical function than their female counterparts.

Exceptional Longevity in Men

Modifiable Factors Associated With Survival and Function to Age 90 Years

Laurel B. Yates, MD, MPH; Luc Djoussé, MD, MPH, DSc; Tobias Kurth, MD, ScD; Julie E. Buring, ScD; J. Michael Gaziano, MD, MPH

Arch Intern Med. 2008;168(3):284-290.

Background Prospective data on nongenetic determinants of exceptional longevity are limited, and information on long-lived men and their functional status is particularly sparse. We examined modifiable factors associated with a life span of 90 or more years and late-life function in men.

Methods In this prospective cohort study of 2357 healthy men (mean age, 72 years) within the Physicians' Health Study (1981-2006), biological and lifestyle factors and comorbid conditions were assessed by self-report with baseline and annual questionnaires. Mortality and incidence of major diseases were confirmed by medical record review. Late-life function was assessed 16 years after baseline by the Medical Outcomes Study 36-Item Short-Form Health Survey.

Results A total of 970 men (41%) survived to at least age 90 years. Smoking was associated with increased risk of mortality before age 90 years (hazard ratio [HR]; 2.10; 95% confidence interval [CI], 1.75-2.51), and similar associations were observed with diabetes (HR, 1.86; 95% CI, 1.52-2.26), obesity (HR, 1.44; 95% CI, 1.10-1.90), and hypertension (HR, 1.28; 95% CI, 1.15-1.43). Regular exercise was associated with a nearly 30% lower mortality risk (HR, 0.72; 95% CI, 0.62-0.83). The probability of a 90-year life span at age 70 years was 54% in the absence of smoking, diabetes, obesity, hypertension, or sedentary lifestyle. It ranged from 36% to 22% with 2 adverse factors and was negligible (4%) with 5. Compared with nonsurvivors, men with exceptional longevity had a healthier lifestyle (67% vs 53% had 1 adverse factor), had a lower incidence of chronic diseases, and were 3 to 5 years older at disease onset. They had better late-life physical function (mean ± SD score [maximum 100], 73 ± 23 vs 62 ± 30; P < .001) and mental well-being (mean score, 84 ± 14 vs 81 ± 17; P = .03). More than 68% (vs 45%) rated their late-life health as excellent or very good, and less than 8% (vs 22%) reported fair or poor health (P < .001 for trend). Regular exercise was associated with significantly better—and smoking and overweight with significantly worse—late-life physical function. Smoking also was associated with a significant decrement in mental function.

Conclusion Modifiable healthy behaviors during early elderly years, including smoking abstinence, weight management, blood pressure control, and regular exercise, are associated not only with enhanced life span in men but also with good health and function during older age.

Kin Selection and Aging

Kin Selection and the Evolutionary Theory of Aging
Andrew F.G. Bourke

Annual Review of Ecology, Evolution, and Systematics
Vol. 38: 103-128

Abstract:Researchers are increasingly recognizing that social effects influence the evolution of aging. Kin selection theory provides a framework for analyzing such effects because an individual's longevity and mortality schedule may alter its inclusive fitness via effects on the fitness of relatives. Kin-selected effects on aging have been demonstrated both by models of intergenerational transfers of investment by caregivers and by spatially explicit population models with limited dispersal. They also underlie coevolution between the degree and form of sociality and patterns of aging. In this review I critically examine and synthesize theory and data concerning these processes. I propose a classification, stemming from kin selection theory, of social effects on aging and describe a hypothesis for kin-selected conflict over parental time of death in systems with resource inheritance. I conclude that systematically applying kin selection theory to the analysis of the evolution of aging adds considerably to our general understanding of aging.

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

Epigenetics and aging

Epigenetics may be defined as changes in gene frequencies without alterations in DNA nucleotide sequences. Generally this occurs with DNA methylation or in some cases what is termed hypermethaltion and histdone modifications. As a person ages these epigentic effects are more likely to occur and may lead to the formation of cancerous tumors. A current article, "Epigenetics and aging: the targets and the marks" by Friga and Esteller (2007) in Trends in Genetics has a good overview of aging and and the epigenetics.

‘Aging epigenetics’ is an emerging field that promises exciting revelations in the near future. Here we focus on the functional and biological significance of the epigenetic
alterations that accumulate during aging and are important in tumorigenesis. Paradigmatic examples are provided by the global loss of DNA methylation in aging
and cancer and by the promoter hypermethylation of genes with a dual role in tumor suppression and progeria, such as the Werner syndrome (WRN) and lamin A/C genes. Another twist is provided by sirtuins, a family of NAD-dependent deacetylases that act on Lys16 of histone H4, which are emerging as a link between cellular transformation and lifespan.

As we begin know about the inner workings of the genome, it is interesting proposition to begin to understand how cells age biologically and this has important implications on how we treat complex chronic degenerative disorders (CDDs). If you take the example of Werner syndrome mentioned in this article and the use of MZ twins you find a large genetic component to aging. The interesting facts that this article go into are that the DNA promoter hypermethylation is implicated in a number of CDDs, including cataracts, Type II diabetes, osteoporosis, various forms of arteriosclerosis, hypogonadism, as well as cancer. What this process is doing is turning off genes that have important implications for normal cellular functioning but by effectively shutting down the promoters it causes havoc in the cell. However, a number of questions need to be answered, such as how heritable are traits and what is the influence of environment on the process. Although as with most scientific endeavors the more we find out about these things the less we seem to know.

References Cited

Fraga MF, M Esteller (2007) Epigenetics and aging: the targets and the marks. Trends in Genetics (23) 8, 413-418

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.

How Low Can You Go?

A common dogma of the medical community is that it is best to reduce your levels of cholesterol as low as possible or at least what is determined low density lipoprotein cholesterol (bad cholesterol). This is simply a fallacy as that cholesterol places such an important part of several biochemical pathways in the body and as transport mechanism. A recent journal article from Journal of the American College of Cardiology (JACC) and mentioned in Science Daily a couple of days ago suggests that low levels of LDL may increase the the likelihood of cancers. The primary aim of statins (drugs that lower cholesterol) and the way they work impacts the formation of LDL in the liver. There are drawbacks to this study which the authors clearly address.

Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer: Insights From Large Randomized Statin Trials

Alawi A. Alsheikh-Ali, Prasad V. Maddukuri, Hui Han, Richard H. Karas

In large randomized statin trials, we found no significant relationship between magnitude of low-density lipoprotein cholesterol (LDL-C) lowering and rates of elevated liver enzymes or rhabdomyolysis. For any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels, but no such association with percent or absolute LDL-C reduction. Hence, drug and dose-specific effects are likely more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low LDL-C may in part be offset by an increased cancer risk.

There is growing evidence (Karlamangla et al., 2004, Brescianini et al., 2003; Iribarren et al., 1995; Schatz et al., 2001; Schupf et al., 2005; Volpato et al., 2001; Weverling-Rijnsburger et al., 1997, Melton et al. 2006) that there may be a threshold for cholesterol in the body, so if you have too little cholesterol you can die from cancer and if it is too high you kick off from heart disease. As heart disease continues to be the leading cause of mortality in the US and a growing problem in the rest of the word it will become increasingly important to understand the underlying complex genetic interactions that characterize cholesterol levels in humans.

References

Brescianini S, Maggi S, Farchi G, Mariotti S, Di Carlo A, Baldereschi M, Inzitari D. 2003. Low total cholesterol and increased risk of dying: are low levels clinical warning signs in the elderly? Results from the Italian Longitudinal Study on Aging. J Am Geriatr Soc 51: 991–996.

Iribarren C, Reed DM, Chen R, Yano K, Dwyer JH. 1995. Low serum cholesterol and mortality. Which is the cause and which is the effect? Circulation 92:2396–2403.

Karlamangla AS, Singer BH, Reuben DB, Seeman TE. 2004. Increases in serum non-high-density lipoprotein cholesterol may be beneficial in some high-functioning older adults: MacArthur Studies of Successful Aging. J Am Geriatr Soc 52:487–494.

Melton PE, M. Zlojutro, K Kimminau, MH Crawford (2006) "Biological Aging and Cox hazard analysis of mortality trends in a Mennonite community from south-central Kansas" American Journal of Human Biology 18(3):387-401.

Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. 2001. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet 358:351–255.

Schupf N, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R. 2005. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc 53:219–226.

Volpato S, Leveille SG, Corti MC, Harris TB, Guralnik JM. 2001. The value of serum albumin and high-density lipoprotein cholesterol in defining mortality risk in older persons with low serum cholesterol. J Am Geriatr Soc 49: 1142–1147.

Weverling-Rijnsburger AW, Blauw GJ, Lagaay AM, Knook DL, Meinders AE, Westendorp RG. 1997. Total cholesterol and risk of mortality in the oldest old. Lancet 350: 1119–1123.