A Modest Gain in Mouse Lifespan via Pharmacological Means of CISD2 Upregulation

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.


Hey there! Just a 2 cents.

Off topic/TL DR: Researchers running out of steam.

I think that right now, scientists/researchers are starting to sound like a (scratched) used (recorded 33-turn vinyl) disc, that skips ....and replays the same tune/part over and over. In a circular (disc).

Circular thinking, back to same point/square 1/start (of circle/lap).
There's no more thinking out of the box, much.

I mean SENS is still one of the most comprehensive undertakings...but, besides that, I don't see what is the next (best) thing..

Scientists/Researchers (of which I am not one..and could never do better than them...am not complaining, for complaining; ranting for ranting; it's still miraculous we get something/they invent these marvels..); it's just not enough...never enough. I would like to say : ''It's Enough...you Done it''. But it's not.

Now, it's Full-Blown (if almost only that) into 'Healthy Aging' and 'healthspan' increasing. Which is highly commendable.

But, they have (almost) abandonned to whole longevity thing...

Because, running out of ideas, running out of steam; ''Don't know...anymore''...

I won't say it is defeat; but it's starting to look a lot like it. Here we thought we would defeat aging; it's starting to look more, the inverse, aging has us defeated (once more) -- like always, (as) it has been (always).

I still sometimes (rarely) check the 'Impact Aging' online issue...this was one of the best ones about Longevity, not healthspan bs, some 10-15 years ago...I loved checking all the great findings that showed that Longevity and Extreme Longevity/Lifespan were not some pipedream; only for some animals...but something possible in humans (too).
Now, it's filled with healthy aging stuff...it's that, basically...there are almost 0 new findings about longevity;...more calorie restriction bs, more cancer research (at least that's good...but a never ending money pit);...Tons of 'Observational Redundant' research...like there are still studies about resveratrol --- today......'likkkeee????'. Oh..and forgot, senolytics.....all this is Fine and great...but will never make anyone live past 130 or so.

The last big ones were epigenetic clock/Yamanaka...and that's about it....there has been 0 advancement to REPAIR DNA DSBs DAMAGE...you know..that (real) damn cause of aging...

As for SENSE Adg...well at least there is lots of great there...but even that is starting to sound redundant...but it shows promise (from WILT to lipofuscin degradation...there is some good there...) it will take a TON of stuff to defeat aging...it's clear. There's just an inordinat amout of things we must do/intake...to fix aging; it will Have to be a multi-approach 'one time thing - each whatever days'...no other way. (and on top of the fact that the epigenetic clock rapidly reverses to 'aged'...if you stop reversing it -- meaning it must be 'maintained reversed' - daily...).

That's an Astronomical undertaking...but what else is there to do, the other thing is accepting defeat and aging would have won (again/as always -- lord/god has outwitted us, again).

Just a 2 cents.

PS: It's looking Definitely 50 years...before we defeat aging...and it's a IF, not an assured 100% thing...it could be 100 years or more now. ''There are discoveries Each New Month...''. yes..but,
''Oasis...Mirage...we close-in...but the mirage recedes...illusion/make belief/'doing 'on place' 'walking'/parked..''. We are trying to gravite the mount everest -- but it's about 1 heptatillion of an octatillion of a decatillion times this mount, in size (in other words, about, infinite (exponent) sized); and why we may never reach this 'aging mount's' top (many climbers...perish half-way or not even quarter-way; just abandon and die there (or get buried by avalanche/fall in crevice)). We can't give up but we are seeing that futility is becoming the word to heed, more so than impossibility (impossible odds, like playing ultra-lotomax'ed for the 1 billion jackpot; in the best(est) scenario/odds, you have about
1 chance out of 7 billion).

Posted by: CANanonymity at August 6th, 2022 12:27 PM

Altos Labs breaks the silence: '20 years and we can prevent aging '

Posted by: Alex at August 6th, 2022 2:59 PM

Hi Alex! Thank your for that. Just a 2 cents.

''Altos Labs insists mission is to improve lives not cheat death;
Hans Bishop, argued, that Altos Labs was working on increasing the "healthspan" of humans and that longevity extension would only be "an accidental consequence". (january 2022)

If they, now, say that can prevent aging in 20 years; perhaps it could be true (20 years...is still a long while); but I have to hold my breath only a little (cause I could not hold my breath at all, for this happening). Though, they have prominent people (including S. Horvath the epiclock guy himself and Yamanaka himself too; the epigenetic reprogrammer) and received billions of donations (from Mr. Bezos Amazon); so they might make it with so much money at them. I only hope they start working on DNA damage because if not, I highly doubt it will lead to prevent aging; but, as they said/Mr. Bishop said, ''insists mission is to improve lives not cheat death''. It better be (more than) ''accidental consequences''; because that really means it's not their intent. If it happens great (plus/bonus), if not...great too. (but not so great to all of us..including them). I don't understand why they are so against it; liike, I can understand that ''it's impossible and we don't want to give false hopes/look like charlatans peddling pseudoscience''...I understand that; but when push comes to shove -- and dying happens ----- they will die; too. That's why..it's like...you got Billions of Dollars from donators...Spend and Burn that cash...because Otherwise; it'S 100% assured -- you (and everyon on earth) dies (including Mr. Bezos or Mr. Bishop, etc). Then..what good is billions...when you are 6 feet underground. ''I don't want to lose my billions in bad investment...I was burned before...so I don't invest in any pseudo research---unless tangible''..it's understandable...but, at certain point, you Must throw the money, because billions or not; you will die 'with your billions'...(is that really better, than 'trying' to defeat aging; as they are doing...but, are very modest about it: ''Altos Labs was working on increasing the "healthspan" of humans and that longevity extension would only be "an accidental consequence").

Just a 2 cents.

PS: If I had billions, I would not have them long. Burnt on whatever that shows promise; it's not lost...nope; because if 'not spent'...it's, again, 100% certain you die. I rather die poor - trying (and possibly making that leap of faith a reality/that big investment gamble...on life)...than die- rich/full of dough. Money = Time = Money = Time. Money can buy you time if you run out of Time --> Life. That means putting the money where it matters (like Alto Labs donations). I think there is huge cynicism and 'been burned in the past', and it's why investors will not invest in something that looks bunk (like 99% of the rest, also). IF with these billion dollars they can't defeat aging...it's not looking good. Hopefully, they will in 20 years or so...

Posted by: CANanonymity at August 6th, 2022 8:50 PM
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