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

The Issues of Antioxidant Therapy

Abstract Interest in antioxidants and antioxidant therapy has been growing during the last decade. Antioxidants are generally considered to have the capability to protect people from harmful effects of reactive oxygen and nitrogen species (RONSs), including free radicals (FR), when these are present in excessive amounts. RONS and free radicals perform a variety of useful biological functions in the body. Their excess is controlled by a natural antioxidant protection system in humans. This protection is provided at three levels: by simple molecules (such as cysteine, glutathione (GSH), uric acid, ubiquinol, etc.), medium-molecular weight, and high molecular weight compounds (enzymes, etc.). Under certain adverse conditions, this system does not manage to provide adequate protection and the RONSs and free radicals begin to damage vital DNA, proteins, and lipids. In such a case, antioxidant therapy, which includes antioxidant supplements and foods containing natural antioxidants, has been suggested to be of possible benefit. However, there are many unresolved issues related to the effective use of an antioxidant therapy: 1. A person should know the content of antioxidants in everyday food products and its relation to the storage time and processing methods used. 2. How many antioxidants should a person consume? It is known that at high concentrations some antioxidants become pro-oxidants. 3. Are the antioxidants consumed by a person bioavailable and, if so, to what extent; for some food products, bioavailability has already been determined but most foods have not been examined. 4. Many antioxidants are digested by intestinal microflora before they reach the systemic blood circulation. 5. Even those antioxidants that do reach the blood are often rapidly metabolized; the role of their metabolites is unclear; there is some evidence that certain metabolites are also antioxidants. 6. How long do antioxidants and their metabolites stay in the body; how are they distributed in different organs; and when are they excreted? In order to answer these questions, the pharmacokinetics of antioxidants should be studied. 7. The presence of oxidative stress, i.e., excess amounts of RONSs and free radicals, can be detected by various oxidative stress markers but, in order to see the whole picture, the actual concentrations of RONSs Am

2001: Melatonin increases both life span and tumor incidence in female CBA mice. The Journals of Gerontology

From the age of 6 months until their natural deaths, female CBA mice were given melatonin with their drinking water (20 mg/l) for 5 consecutive days every month. Intact mice served as controls. The results of this study show that the consumption of melatonin did not significantly influence food consumption, but it did increase the body weight of older mice; it did not influence physical strength or the presence of fatigue; it decreased locomotor activity and body temperature; it inhibited free radical processes in serum, brain, and liver; it slowed down the agerelated switching-off of estrous function; and it increased life span. However, we also found that treatment with the used dose of melatonin increased spontaneous tumor incidence in mice. For this reason, we concluded that it would be premature to recommend melatonin as a geroprotector for long-term use