A Systems Approach to Reverse Engineer Lifespan Extension by Dietary Restriction

Abstract

Summary Dietary restriction (DR) is the most powerful natural means to extend lifespan. Although several genes can mediate responses to alternate DR regimens, no single genetic intervention has recapitulated the full effects of DR, and no unified system is known for different DR regimens. Here we obtain temporally resolved transcriptomes during calorie restriction and intermittent fasting in Caenorhabditis elegans, and find that early and late responses involve metabolism and cell cycle/DNA damage, respectively. We uncover three network modules of DR regulators by their target specificity. By genetic manipulations of nodes representing discrete modules, we induce transcriptomes that progressively resemble DR as multiple nodes are perturbed. Targeting all three nodes simultaneously results in extremely long-lived animals that are refractory to DR. These results and dynamic simulations demonstrate that extensive feedback controls among regulators may be leveraged to drive the regulatory circuitry to a younger steady state, recapitulating the full effect of DR.

A Polymer Model with Epigenetic Recolouring Reveals a Pathway for the de novo Establishment and 3D organisation of Chromatin Domains

“…The inactivation process is achieved, in practice, through the spreading of repressive histone modifications, which turn the chromosome into a transcriptionally silenced Barr body [7][8][9]. This is an example of an "epigenetic switch", a term which generically refers to the up or down-regulation of specific genes in response to, e.g., seasonal changes [10][11][12], dietary restrictions [13], aging [14] or parental imprinting [15].…”

The system capacity view of aging and longevity

“…Both i) and ii) can be achieved through targeting the different system components of an organism (such as energy and material generation and selfmaintenance components), or through reducing the intrinsic (such as reproduction and metabolism) and extrinsic demands (such as exposure to damaging materials) ( Figure 3B). Most strategies fall into the first category, including genetic, pharmaceutical and dietary perturbations through nutrient-sensing pathways, stress response pathways, sirtuins or some epigenetic factors to boost self-maintenance programs [9,15,[28][29][30][31]. Mitochondria defects during development in C. elegans, which probably shape the system capacity through mitohormesis, probably belong to the second category [20].…”

“…For instance, the post-reproduction stage seems to be a transition point for one of the three major transcriptome patterns during aging, PC2 ( Figure 1B). The expression levels of cell cycle and DNA damage repair genes progressively increase during development, peak post reproduction and decline afterwards [9]. DR/IF slightly and significantly shifted the maximal expression levels of these genes at the turning points ( Figure 1C).…”

“…Gene expression profile changes during aging upon caloric restriction. Average gene expression profiles of clusters that change with age under ab libitum (AL) condition (blue curves) and two dietary restriction regimens, including calorie restriction (CR) (red curves) and intermittent fasting (IF) (green curves), adapted from Figure S1 in our previous study [9]. Gene ontology terms enriched in each gene cluster are shown.…”

“…They are related to i) (de)phosphorylation, ii) redox metabolism and unfolded protein response (UPR), and iii) cell cycle and DNA damage responses, respectively [9]. The maximal or minimal expression levels of gene expression groups altered by CR/IF suggest that they not only cause a delay in age-dependent changes, but also change the maximal or minimal levels of the gene functions, or capacities, of these gene functions ( Figure 1).…”