Economic progress as cancer risk factor. II: Why is overall cancer risk higher in more developed countries?

Analysis of data on cancer incidence rates in different countries at different time periods revealed positive association between overall cancer risk and economic progress. Typical explanations of this phenomenon involve improved cancer diagnostics and elevated exposure to carcinogens in industrial countries. Here we provide evidence from human and experimental animal studies suggesting that some other factors associated with high economic development and Western life style may primarily increase the proportion of susceptible to cancer individuals in a population and thus contribute to elevated cancer risks in industrial countries. These factors include (but not limited to): (i) better medical and living conditions that “relax” environmental selection and increase share of individuals prone to chronic inflammation; (ii) several medicines and foods that are not carcinogenic themselves but affect the metabolism of established carcinogens; (iii) nutrition enriched with growth factors; (iv) delayed childbirth. The latter two factors may favor an increase in both cancer incidence rate and longevity in a population. This implies the presence of a trade-off between cancer and aging: factors that postpone aging may simultaneously enhance organism’s susceptibility to several cancers. Key words: cancer risk, individual susceptibility, economic progress, aging

Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: Insights on mechanisms from the long life family study

The lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR](>75)=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR(>76)=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(−3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span

Composite measure of physiological dysregulation as a predictor of mortality: The Long Life Family Study

Biological aging results in changes in an organism that accumulate over age in a complex fashion across different regulatory systems, and their cumulative effect manifests in increased physiological dysregulation (PD) and declining robustness and resilience that increase risks of health disorders and death. Several composite measures involving multiple biomarkers that capture complex effects of aging have been proposed. We applied one such approach, the Mahalanobis distance (

Dynamic Determinants of Longevity and Exceptional Health

It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth. We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. These newly identified variables are promising targets for prevention aiming to postpone onsets of common elderly diseases and increase longevity

How Well Does the Family Longevity Selection Score Work: A Validation Test Using the Utah Population Database

The Family Longevity Selection Score (FLoSS) was used to select families for the Long Life Family Study (LLFS) but has never been validated in other populations. The goal of this paper is to validate how well the FLoSS-based selection procedure works in an independent dataset. In this paper, we computed FLoSS using the lifespan data of 234,155 individuals from a large comprehensive genealogically-based resource, the Utah Population Database (UPDB), born between 1779 and 1910 with mortality follow-up through 2012–2013. Computations of FLoSS in a specific year (1980) confirmed the survival advantage of the “exceptional” sibships (defined by LLFS FLoSS threshold, FLoSS ≥ 7). We found that the subsample of the UPDB participants born after 1900 who were from the “exceptional” sibships had survival curves similar to that of the US participants from the LLFS probands' generation. Comparisons between the offspring of parents with “exceptional” and “ordinary” survival showed the survival advantage of the “exceptional” offspring. Investigators seeking to explain the extent genetics and environment contribute to exceptional survival will benefit from the use of exceptionally long-lived individuals and their relatives. Appropriate ranking of families by survival exceptionality and their availability for the purposes of providing genetic and phenotypic data is critical for selecting participants into such studies. This study validated the FLoSS as selection criteria in family longevity studies using UPDB

An ancient bison from the mouth of the Rauchua River (Chukotka, Russia)

An incomplete carcass of an extinct bison, Bison ex gr. priscus, was discovered in 2012 in the mouth of the Rauchua River (69°30'N, 166°49'E), Chukotka. The carcass included the rump with two hind limbs, ribs, and large flap of hide from the abdomen and sides, several vertebrae, bones of the forelimbs and anterior autopodia, stomach with its contents, and wool. The limb bones are relatively gracile, which is unusual in bison, and a SEM study of the hair microstructure suggests higher insulating capacity than in extant members of the genus. Additionally, mitochondrial DNA analyses indicate that the Rauchua bison belonged to a distinct and previously unidentified lineage of steppe bison. Two radiocarbon dates suggest a Holocene age for the bison: a traditional 14C date provided an estimate of 8030±70 14C yr BP (SPb-743) and an AMS radiocarbon date provided an age of 9497±92 14C yr BP (AA101271). These dates make this the youngest known bison from Chukotka. Analysis of stomach contents revealed a diet of herbaceous plants (meadow grasses and sedges) and shrubs, suggesting that the early Holocene vegetation near the mouth of the Rauchua River was similar to that of the present day: tundra-associated vegetation with undersized plants

Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan

Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6×10(−6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0×10(−7)). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3×10(−8)) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms

Economic progress as cancer risk factor. II: Why is overall cancer risk higher in more developed countries?

Analysis of data on cancer incidence rates in different countries at different time periods revealed positive association between overall cancer risk and economic progress. Typical explanations of this phenomenon involve improved cancer diagnostics and elevated exposure to carcinogens in industrial countries. Here we provide evidence from human and experimental animal studies suggesting that some other factors associated with high economic development and Western life style may primarily increase the proportion of susceptible to cancer individuals in a population and thus contribute to elevated cancer risks in industrial countries. These factors include (but not limited to): (i) better medical and living conditions that "relax" environmental selection and increase share of individuals prone to chronic inflammation; (ii) several medicines and foods that are not carcinogenic themselves but affect the metabolism of established carcinogens; (iii) nutrition enriched with growth factors; (iv) delayed childbirth. The latter two factors may favor an increase in both cancer incidence rate and longevity in a population. This implies the presence of a trade-off between cancer and aging: factors that postpone aging may simultaneously enhance organism's susceptibility to several cancers. Key words: cancer risk, individual susceptibility, economic progress, agin