18 March 2009

Life extension, starvation and gene expression

How periodic fasting increases life expectancy
Anna Sablina, EternalMind.ruThe effect of radical calorie restriction on life expectancy has been known for a long time.

Japanese scientists have found that periodic fasting also increases life expectancy, and through a signaling pathway different from that for general calorie restriction.

Dietary restrictions are the most effective means of increasing the life expectancy of animals of various species. In mammals, the effectiveness in increasing life expectancy and slowing down age-related diseases has been proven for two types of dietary restrictions: periodic fasting (intermittent fasting, IF) and chronic calorie restriction (caloric restriction). With the first type of regime, part of the time there are no restrictions on food intake, the other part of the time the body is subjected to starvation. Such a regime can increase life expectancy even when the total calorie intake decreases slightly or does not decrease at all. The very absence of food can serve as a signal in determining life expectancy, independent of the total number of calories consumed and even more powerful. Studies have shown that these signals go through different molecular pathways.

A group of Japanese scientists from Kyoto University managed to develop a periodic fasting regime that prolongs the life of the roundworm Caenorhabditis elegans, which is the first case of developing such a regime for invertebrates. This object is the most convenient and most often used in the study of aging, especially its molecular mechanisms. Complete deprivation of food for every second or every third day increased the life expectancy of this organism by 40 and 56%, respectively. Such a diet also increased resistance to thermal and oxidative stress, and also noticeably slowed down the age-related physiological "extinction". Researchers have shown that in this object, the small GTPase RHEB-1 plays a dual role in regulating life expectancy. This protein is necessary to increase life expectancy caused by periodic fasting, but its inhibition mimics the effect of calorie restriction, which in such animals does not manifest itself in an increase in life expectancy. RHEB-1 is expressed in C. elegans throughout the body, from the earliest stages of development to adulthood. This expression is activated in response to starvation and is inhibited by subsequent feeding. Periodic fasting increases life expectancy much more than constant calorie restriction, but its effect is not manifested in animals with inhibition of RHEB-1 expression by RNA interference.

Complex and ambiguous ways linking diet with life expectancy.

RHEB-1 exerts its effect on life expectancy mainly through the activation of the TOR protein. This is a signaling protein, the activity of which decreases during fasting and artificial inhibition of which leads to an increase in life expectancy, similar to that with calorie restriction of food. In animals with inhibition of TOR expression, the effect of periodic fasting is still manifested, although weaker than in the wild type. The signaling pathways of the RHEB-1 and TOR proteins are complex and ambiguous, for example, they contribute to an increase in total protein synthesis, and the lifespan, at least in roundworms, increases with its decrease

The daf-16 protein is also necessary to increase the lifespan of worms during periodic starvation. It belongs to the transcription factors of the forkhead family and mediates the effect of signaling pathways of insulin-like growth factors on aging. Stressful conditions, which include fasting, trigger its movement into the cell nucleus. RHEB-1 and TOR are necessary for this movement and activation of DAF-16 targets. Thus, DAF-16 mediates, at least partially, the signaling functions coming from RHEB-1 with an increase in life expectancy associated with periodic fasting.

The molecular mechanisms of periodic fasting and calorie restriction are different. Thus, the expression levels of the rab-10 and pha-4 genes, the expression level of the first of which decreases and the second increases with calorie restriction, do not change with periodic fasting. With the RNA interference of RHEB-1 and TOR, the expression level of pha-4 increases, which may indicate that with calorie restriction (but not with periodic fasting), signaling goes through this protein. It is also known that the effect of increasing life expectancy with overexpression of pha-4 does not depend on daf-16. Most likely, the signal path is branching directly "downstream" from RHEB-1 and TOR.

Using the microarray method, the researchers found out that during fasting in C. elegans, the expression of 112 genes increases by more than 3 times, for the vast majority of which this increase depended on both RHEB-1 and TOR. The increased expression of 18 genes depended on RHEB-1, but not on TOR, which may indicate the beginning of the RHEB-1 TOR-independent signaling pathway leading to an increase in life expectancy during periodic fasting. One of the genes whose induction during fasting depends on RHEB-1 and TOR — hsp-12.6, which in C. elegans encodes the orthologue of the small heat shock protein aB-crystallin. It is very likely that hsp-12.6 is one of the targets of daf-16.

It is known that mutants in which the daf-2 protein is inactive live for a long time. Their reduced level of insulin/IGF-like peptides entails constitutive activation of daf-16 and higher expression of hsp-12.6 than in the wild type. In these mutants, periodic fasting does not noticeably prolong life expectancy. This suggests that periodic fasting acts through the weakening of daf-2 activity. The data of these researchers confirm the idea that at the molecular level, the effects of periodic fasting are determined by a decrease in the activity of the daf-2 signaling pathway, which leads to the activation of daf-16, hsp-12.6 and hsf-1.

The expression of 298 genes in C. elegans decreased by more than 3 times during periodic fasting. Of these, the activity of only one gene, ins-7 (insulin-like), increased after fasting with RHEB-1 and TOR RNA interference compared to the control. It has been shown that the product of this gene reduces life expectancy by inhibiting the activity of daf-16 through daf-2, therefore, a decrease in its amount caused by starvation may be a mechanism for increasing life expectancy. However, there are other insulin-like peptides that compensate for ins-7 when it is deleted, so that the suppression of the effect of periodic fasting on life expectancy is small. Fasting reduces their expression. Only when scientists are able to simultaneously suppress the expression of several insulin-like genes, it will be possible to noticeably mimic the positive effect of fasting on life expectancy.

Different protocols for limiting the diet of C. elegans prolong the life of this organism through different molecular pathways. Complete food deprivation increases life expectancy independently of daf-2 and daf-16, although this regime resembles periodic fasting. DAF-16 moves to the nucleus in response to starvation, but returns to the cytoplasm when fasting for more than 2 days. It is known that the constant restriction of the diet in C. elegans is mediated by the daf-16 protein, whose upstream regulator is aak-2, an AMPK orthologue, but it is not necessary to increase life expectancy during periodic fasting, daf-2 acts instead.

Knowledge of the relative effectiveness in the fight against senile diseases and the molecular mechanisms of various types of dietary regimens may help in the future in the development of pharmacological drugs to increase life expectancy.

Source: Sakiko Honjoh, Takuya Yamamoto, Masaharu Uno & Eisuke Nishida Signaling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans // Nature, Vol 457, P. 726-731, 5 February 2009, DOI: 10.1038/nature 07583

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