The usual progression of ways to tinker with metabolism in order to affect the pace of aging is much as follows: (a) identify an interesting mechanism associated with a single gene; (b) create mouse lineages in which the expression of this gene is manipulated in a controlled way via genetic engineering, to observe the outcomes; (c) use some form of gene therapy to overexpress or knock down that gene in mice, and note differences in life span and manifestations of aging; (d) search the drug databases for small molecules that might affect expression of the gene of interest without causing too many undesirable side-effects; (e) produce animal studies to show that the small molecule approach produces the same outcome as the genetic studies, but to a smaller degree.

If further development is then undertaken, it typically picks up from the small molecule demonstration, which is almost always unimpressive in comparison to the gene therapy. The economics of development still heavily favor working with small molecules, however, to the point at which producing a marginal therapy that is less likely to help patients is an acceptable cost of doing business. This is particularly the case since early investors typically make their returns, and are on to the next project, well before the issues associated with marginal effect sizes arise in phase II or phase III clinical trials. It is a broken system, and the obvious fix, that most small molecule development should in fact be gene therapy development, is slow in arriving. Gene therapies must fall in cost by a sizable amount to be competitive in this way.

Today’s open access paper is an example of step (e) noted above in ongoing research into the role of CISD2 in aging. Researchers have in in the past demonstrated that CISD2 decreases in expression with age, and that producing mice that overexpress CISD2 extends their life span. This effect may arise because CISD2 influences autophagy and mitochondrial function, but like most longevity-associated genes, it participates in many cellular processes, and picking apart the relevant from the irrelevant is a challenging task. Here, researchers are trying to manipulate CISD2 with non-genetic means, and in doing so produce the predictably modest extension of life span in mice. If autophagy and other stress response mechanisms are the primary way in which CISD2 upregulation produces life extension, then it is unlikely to have any meaningful effect on life span in humans. Even given that the intervention in this study was started in late life, it is well known that this sort of calorie restriction mimetic approach works very much better in short-lived species than in long-lived species such as our own.

Hesperetin promotes longevity and delays aging via activation of Cisd2 in naturally aged mice

The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging.

Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age.

Hesperetin is the first compound we have tested as a proof-of-concept for the hypothesis that a Cisd2 activator will have an anti-aging effect. Our findings provide an experimental basis for using Cisd2 as a molecular target for the screening and development of novel compounds that are able to activate Cisd2 pharmaceutically with the goal of translating these drugs into clinical interventions that can be used in geriatric medicine. Most importantly, hesperetin can be rapidly delivered systematically to multiple organs and tissues in vivo. Additionally, it has no detectable in vivo toxicity after long-term oral administration for 6-7 months in mice, specifically when supplemented in food at a dose of 100 mg/kg/day, which has a human equivalent dose of 491 mg/60 kg/day. Accordingly, it will be of great interest to develop hesperetin as a medicinally or nutritionally functional food for preventive purposes related to extending healthy lifespan and/or therapeutic purpose related to treating age-related diseases.

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