Stress resistance and aging: Influence of genes and nutrition

Abstract

Previous studies have shown that dermal fibroblast cell lines derived from young adult mice of the long-lived Snell dwarf (dw/dw), Ames dwarf (df/df) and growth hormone receptor knockout (GHR-KO) mouse stocks are resistant, in vitro, to the cytotoxic effects of hydrogen peroxide, cadmium, ultraviolet light, paraquat, and heat. Here we show that, in contrast, fibroblasts from mice on low-calorie (CR) or low methionine (Meth-R) diets are not stress resistant in culture, despite the longevity induced by both dietary regimes. A second approach, involving induction of liver cell death in live animals using acetaminophen (APAP), documented hepatotoxin resistance in the CR and Meth-R mice, but dw/dw and GHR-KO mutant mice were not resistant to this agent, and were in fact more susceptible than littermate controls to the toxic effects of APAP. These data thus suggest that while resistance to stress is a common characteristic of experimental life span extension in mice, the cell types showing resistance may differ among the various models of delayed or decelerated aging.

Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients

“…Contrary to this dogma, many studies suggest that a 20-40% reduction in calorie intake protects the host against toxins and retards the growth of tumors (Moreschi, 1909;Tannenbaum, 1945;Hursting et al, 1994Hursting et al, , 2001Hursting et al, , 2003Fontana et al, 2001Fontana et al, , 2006Harper et al, 2006;Bonorden et al, 2009;Colman et al, 2009;Longo and Fontana, 2010). However, this has never been translated into clinical applications because the effects are limited, as reduced calorie intake unavoidably causes weight loss, and because it was not clear that DR could not also protect cancer cells from chemotherapy.…”

“…However, fasting still poses a challenge to patients, which calls for an urgent need of substitution diets or targeted drugs that can mimic fasting. Experimental evidence from aging research suggests that diets with specific deficiencies, especially essential amino acids, may provide increased stress resistance and lifespan (Richie et al, 1994;Takenaka et al, 2000;Harper et al, 2006). Although, it is unlikely that the vast effects caused by fasting can be obtained with specific deficiencies, it will be important to determine whether limitations of specific nutrients will be sufficient to promote some of the effects of fasting.…”

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…Moreover, in some instances, the data obtained failed to directly support a direct role for mitochondrial oxidative stress or oxidative stress in the determination of life span in mice and also did not support the overall free radical theory of aging [337,[342][343][344][345][346]. Although, these various findings are somewhat disappointing, more recent mechanistic studies, however, have clearly implicated the mitochondrial free radical damage and impaired mitochondrial function as being a central contributor to the pathophysiology of aging [347][348][349].…”

“…In recent years, however, the use of transgenic and knockout mouse models with altered expression of antioxidant enzymes and mutant mouse models that have been genetically modified to increase mitochondrial deletions or mutations (Poly D257A/D257A mutant mice) to directly test the validity of the mitochondrial theory of aging have yielded inconsistence results [337,[342][343][344][345][346]. Moreover, in some instances, the data obtained failed to directly support a direct role for mitochondrial oxidative stress or oxidative stress in the determination of life span in mice and also did not support the overall free radical theory of aging [337,[342][343][344][345][346].…”

“…Based on extensive in vivo and in vitro studies, it now appears that senescence is associated with increased oxidant generation, a decline in the robustness of cellular defenses and repair, and an accumulation of the end products of the oxidative damage [331,336,[339][340][341][342][343][344][345][346][347][348][349][350][351][352][353][354]. In general, the three main classes of biological macromolecules (lipids, nucleic acids and proteins) are susceptible to free radical attack and suffer oxidative damage in vivo [331,336,[339][340][341][342][343][344][345][346][347][348][349][350][351][352][353][354].…”