Fight Aging!

The paper I'll point out today reports on the effects of calorie restriction in mice and humans on markers of cellular senescence, one of the contributing cause of aging. Calorie restriction is well known to slow aging and extend life span in a near all species and lineages tested, with that effect being largest in short-lived species. Mice live up to 40% longer when calorie restricted, but in humans it would be surprising to find an effect larger than five years or so - once firm data is in hand, which is not presently the case. Nonetheless, the short term benefits to health and the changes to cellular metabolism produced by the practice of calorie restriction are quite similar across mammalian species of different life spans.

These are sweeping changes: near every measure of metabolic activity and progression of aging is altered by calorie restriction. Given that, it is challenging to identify the size of the contribution of any given mechanism, but it is certainly fair to ask. To what degree does calorie restriction act through a reduction of each of the forms of cell and tissue damage that cause aging? One of the forms of damage is an accumulation of senescent cells. Cellular senescence is a fascinating phenomenon with both positive and negative outcomes; it is beneficial when temporary, as cells briefly become senescent in order to aid in regeneration or reduce the risk of damaged cells becoming cancerous. When senescent cells fail to quickly self-destruct, however, they linger to cause harm to surrounding tissue. Their signals generate chronic inflammation, destroy important molecular structures, and change the behavior of other cells for the worse.

Removing all senescent cells increases mouse life span by 25%, calorie restriction increases mouse life span by 40%, and calorie restricted mice still have some number of senescent cells. From a first glance at the numbers and the existing evidence, reduced cellular senescence can only only account for a modest fraction of the benefits of calorie restriction. In line with that, the paper noted here shows that calorie restricted mice and humans appear to have fewer signs of senescent cell activity, consistent with reductions in all of the other measures of age-related damage under calorie restriction.

The interesting question is how exactly calorie restriction produces this outcome. Fewer cells become senescent? More senescent cells successfully self-destruct? Individual senescent cells are less actively harmful, and their signaling is reduced? One item to bear in mind while thinking about this is the evidence for the benefits of calorie restriction to be absolutely reliant upon autophagy - increased autophagy is a feature of calorie restriction, as well as many other methods of slowing aging, and in animals in which autophagy is disabled, calorie restriction does not improve life span or health. So it seems to me that any consideration of calorie restriction and cellular senescence must in some way involve autophagy.

The effects of graded caloric restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon

While genetic manipulations of model organisms have set important milestones for the understanding of the aging process, calorie restriction (CR) is a well-established nongenetic approach able to improve health span and lifespan in different organisms. However, the precise mechanisms by which CR improves health are not fully understood. More than 50 years ago, cellular senescence was discovered. Subsequent studies demonstrated that senescent cells gradually accumulate with increasing age in various organisms. During aging, senescent cells impair cellular turnover and tissue regeneration due to their inability to proliferate, and stimulate a pro-disease environment by the chronic secretion of various pro-inflammatory and tissue-remodeling factors, a phenotype called Senescence-Associated Secretory Phenotype (SASP).

Genetic and pharmacological elimination of senescent cells is sufficient to improve health span. Interestingly, a previous report suggested that CR prevented accumulation of senescent cells in the mouse liver and intestine. To further explore the potential reduction in senescent cells upon short-term CR, and whether this phenomenon might potentially happen in humans, we analyze various classical transcriptomic markers for senescence and SASP in short-term CR interventions in the mouse and human colon mucosa specimens.

Male mice were aged 20 weeks when they entered four levels of CR for 12 weeks: 10%, 20%, 30%, and 40% restriction from baseline food intake. The colon of these mice was divided into three regions: proximal, medial, and distal. In the proximal colon, the expression levels of two classical markers of senescence-associated growth arrest, p16 and p21, did not change significantly among groups. Selected markers for the SASP also did not significantly change. In the medial colon, while there were no differences among the two controls and the lowest CR interventions (10%-20%), all markers of senescence were downregulated at higher CR regimens. A similar trend was present in the distal colon. These data suggest that short-term CR at higher levels can prevent or decrease the accumulation of senescent cells in the mouse colon, even in adult but relatively young animals on short-term restriction.

We then sought to determine whether CR modifies the expression levels of senescence and SASP markers in the human sigmoidal colon mucosa. To this end, we recruited and studied 12 middle-aged (61.7 ± 8.4 years), weight-stable very lean (BMI = 19.1 ± 1.3 kg/m2) members of the Calorie Restriction Society who have been practicing ~30% CR with adequate nutrition (at least 100% of RDI for each nutrient) for an average of 10.1 years. Levels of p16 were significantly lower in the CR group. Levels of p21 followed the trend observed in p16, but did not reach statistical significance. In accordance with a previous study, we observed significantly lower level of SASP factors, but only three reached statistical significance. These data suggest that CR could potentially prevent the accumulation of age-associated senescent cells in the colon mucosa of human beings, and the reduction in senescence might explain the much lower levels of inflammation observed in CR individuals.