Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.

Naturally occurring p16 Ink4a -positive cells shorten healthy lifespan

During the past century, treatments for the diseases of youth and middle age have helped raise life expectancy significantly. However, cognitive decline has emerged as one of the greatest health threats of old age, with nearly 50% of adults over the age of 85 afflicted with Alzheimer's disease. Developing therapeutic interventions for such conditions demands a greater understanding of the processes underlying normal and pathological brain ageing. Recent advances in the biology of ageing in model organisms, together with molecular and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline.

/pdf/neural-mechanisms-of-ageing-and-cognitive-decline-17cy984rwm.pdf

Neural mechanisms of ageing and cognitive decline

It has long been suspected that the relative abundance of specific nutrients can affect cognitive processes and emotions. Newly described influences of dietary factors on neuronal function and synaptic plasticity have revealed some of the vital mechanisms that are responsible for the action of diet on brain health and mental function. Several gut hormones that can enter the brain, or that are produced in the brain itself, influence cognitive ability. In addition, well-established regulators of synaptic plasticity, such as brain-derived neurotrophic factor, can function as metabolic modulators, responding to peripheral signals such as food intake. Understanding the molecular basis of the effects of food on cognition will help us to determine how best to manipulate diet in order to increase the resistance of neurons to insults and promote mental fitness.

/pdf/brain-foods-the-effects-of-nutrients-on-brain-function-2cng8bwpxq.pdf

Brain foods: the effects of nutrients on brain function

https://www.cell.com/cell-metabolism/pdf/S1550-4131(11)00386-X.pdf

Calorie Restriction-like Effects of 30 Days of Resveratrol Supplementation on Energy Metabolism and Metabolic Profile in Obese Humans

https://www.healthpromoting.com/sites/default/files/FastingMolecularMechanisms.pdf

Fasting: Molecular Mechanisms and Clinical Applications

Female C3B10RF1 mice maintained on either a control (approximately 95 kcal/week) or restricted (approximately 55 kcal/week) diet since weaning were tested in a behavioral battery at 11 to 15 or 31 to 35 months of age (middle-aged vs. aged). Age-related declines observed among control groups in tests of motor coordination (rotorod) and learning (complex maze) were prevented by the restriction regime. In addition, diet restriction increased locomotor activity in a runwheel cage among mice of both ages but did not affect exploratory activity in a novel arena.

Dietary restriction benefits learning and motor performance of aged mice.

Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age.

From weaning to death, 28 male Wistar rats were maintained on an ad libitum (AL) diet, and 24 counterparts were provided the diet every-other-day (EOD). The mean life span of the EOD group represented an 83% increase over that of the AL group. Furthermore, a Gompertzian analysis of mortality rates suggested that the rate of aging was retarded in the EOD group. While body weight and growth rate were reduced in the EOD group, their growth duration was 75% longer compared to the AL group. Significant positive relationships emerged between life span and growth rate parameters in the AL group; however, no significant relationships were found between life span and body weight parameters in the EOD group. Therefore, in support of the hypothesis that dietary restriction effects prolongevity through retarded development, evidence was produced only in the between-group comparisons of AL- and EOD-fed animals.

Effects of intermittent feeding upon growth and life span in rats.

Foundations of a Policy for the Aged in the 1980s and Beyond

Male wistar rats were housed in laboratory cages or activity-wheel cages at eight 10.5 or 18 months of age. Part of each cage group continued to be fed ad libitum, whereas the remaining animals were fed every other day. Compared with the ad libitum condition, intermittent feeding decreased body weight and increased lifespan at both ages in both caging conditions. Compared with the caged condition, voluntary exercise in activity wheels reduced body weight only in the 10.5-month-old group fed ad libitum but produced no effect on survival of either age group. The results suggest that intermittent feeding can enhance survival in mature rats even beyond ages at which body weight growth usually ceases, whereas voluntary exercise appears to have an early threshold beyond which increases in longevity are not observed.

Differential Effects of Intermittent Feeding and Voluntary Exercise on Body Weight and Lifespan in Adult Rats

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