Short Term Cdc42 Inhibition In Middle Aged Mice Extends Median and Maximum Life Span

An interesting study of mouse life span extension via a novel methodology was recently published. The researchers developed a small molecule approach to inhibition of Cdc42, a protein with numerous functions throughout the cell. This is a target for intervention because - at least in cell cultures - loss of Cdc42 activity appears to restore youthful function to aged hematopoietic stem cells. This is the cell population responsible for producing blood and immune cells, and declining immune function with age is driven at least in part by dysfunction in hematopoietic stem cells. Ways to restore immune function in older individuals should prove to be broadly beneficial to health in later life, given that the immune system has roles in tissue maintenance and function that extend far beyond merely defending against pathogens.

The effect size in mice for Cdc42 inhibition is here shown to be somewhere in the range of a 12-16% gain in median and maximum life spans, along with a reversal of age-related changes in some inflammatory cytokine levels. This gain in life span isn't large in the grand scheme of things, given that lifelong calorie restriction can result in a 40% increase in mouse life span, but the point of interest here is that this result was achieved with a single four day treatment carried out in middle aged mice, already well on the way towards being aged. Only rapamycin and senolytics have robustly achieved similar outcomes based on short term late life treatment.

We might hypothesize that, in these aging mice, the generation of new immune cells by hematopoietic stem cells was increased for long enough via this intervention to provide the lasting benefits of a renewed and bolstered immune system. Even if raised rates of immune cell generation don't last, the additional cells created will last. An aging immune system should be in an incrementally better state going forward as the result of any intervention capable of providing more new immune cells for a time. Unfortunately a full assessment of immune cell populations wasn't carried out in this study; only proximate measures of immune system activity such as cytokine levels were assessed.

Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice

Cdc42 is involved in multiple and diverse functions of eukaryotic cells, including actin cytoskeleton reorganization, cell polarity, and cell growth. The activity of Cdc42 is significantly elevated in blood of elderly humans and in several tissues of aged C57BL/6 mice. We recently identified a specific small-molecule inhibitor of Cdc42 activity termed CASIN. Administration of CASIN in vivo did not show signs of toxicity. Previously, we reported that a brief ex vivo exposure of aged hematopoietic stem cells (HSCs) to CASIN that reduced the activity of Cdc42 in aged cells to the level found in young cells resulted in long-lasting youthful function of HSCs in vivo, likely due to epigenetic remodeling of aged cells upon modulation of Cdc42 activity. Consequently, we hypothesized that maybe a short-term systemic reduction of Cdc42 activity in aged animals in vivo might be also beneficial for lifespan, as an elevated activity of Cdc42 upon aging is causatively linked to a shorter lifespan in mice.

To determine whether a short-term systemic CASIN treatment of aged animals might indeed influence lifespan, we administered CASIN via intraperitoneal injection every 24 hours for 4 consecutive days to 75-week-old female C57BL/6 mice. 4 days of consecutive injections did not induce acute toxicity, and as well, none of the treated mice died within 4 weeks after CASIN injections, rendering chronic toxicity issues unlikely. Quantification of Cdc42 activity 24 hours after the last injection on day 5 demonstrated a reduction of Cdc42 activity in aged bone marrow cells to the level seen in young, confirming that CASIN is indeed reducing Cdc42 activity after a systemic in vivo treatment. Notably, aged mice treated with CASIN for only 4 consecutive days showed extension of their average and also maximum lifespan.

We performed analyses to investigate the extent to which aging-associated inflammatory cytokines in serum of aged mice were affected by CASIN treatment. Data showed a marked increase in the concentrations of INFγ, IL-1β, and IL-1α on aging and the concentrations for these cytokines were similar to concentrations in young animals upon CASIN treatment of aged mice. It is thus a possibility that a reduction in the concentrations of these cytokines upon CASIN treatment might contribute to the increase in lifespan observed in these animals.

Previously, the methylation status of CpG sites within the genes Prima1, Hsf4, and Kcns1 was shown to qualify as likely predictor of biological age of C57BL/6 mice. Applying this C57BL/6-trained DNA methylation marker panel to blood cells from aged animals treated with CASIN 9 weeks after treatment, we observed that epigenetic age predictions did not correlate anymore to the chronological age as in aged control animals, but resulted in a biological age prediction that was on average 9 weeks younger than their chronological age. These data imply that epigenetic changes underlie the extended longevity of aged CASIN-treated mice, while reinforcing the necessity to mechanistically validate tissues, cells, and biological pathways involved in the extension of longevity.

Comments

While the effect size is less than CR it still looks like a simple and rather safe intervention. Even if it doesn't increase the life expectancy it might still increase the healthspan. If we are really lucky the effects might be cumulative with senolytic treatments.

Posted by: cuberat at August 7th, 2020 2:54 PM

This again, like rejuvenation via plasma factors, supports the value of upstream reprogramming vs. downstream damage repair. Seems increasingly likely that, at some point in the future, even relatively late in life, reprogramming to prevent or reverse aging will be considered the preferred approach, with direct damage repair/cleanup being an unfortunate last resort - a very different way of looking at the problem than that first outlined by AdG and followers (i.e., humans not as cars but as complex systems that can be reprogrammed to be less tolerant of the damage that is designed/allowed [by selection] to otherwise limit our life expectancy).

Posted by: dtkamp at August 7th, 2020 7:57 PM

@dtkamp: The most likely causes are both down and upstream and we will get synergistic effects if therapies are developed for both.

Posted by: thomas.a at August 8th, 2020 4:21 AM

"we will get synergistic effects" Yes, and we don't know which will be more effective in the immediate future, esp. for those who already have a lot of damage. But, in the long run, it seems to me that we are already beginning to see that upstream solutions (i.e., not just proximate causes of localized downstream damage, like large amounts of senescent cells or beta amyloid) will be the more effective path. Similar to treating hypertension: is it better to eliminate the higher BP with a drug, or to use diet and exercise to address the problem? The quick solution is to address the problem with a drug, but the better approach is to look further upstream at more fundamental causes and try to address those, producing a much more robust and wider range of downstream benefits. imho

Posted by: dtkamp at August 8th, 2020 8:02 AM

The anti-parasite medication niclosamide, which coincidentally is now in clinical trials for COVID inhibits cdc42.

"Recent studies have indicated that niclosamide has broad applications for cancer and other diseases. In this study, we found that niclosamide could not only inhibit proliferation and promote apoptosis of oral cancer cells, but also inhibited VM formation in vitro and in vivo through downregulation of the expression of VM-related genes VEGFA, MMP2, ROCK1 and Cdc42"
https://www.spandidos-publications.com/10.3892/or.2017.6146

Posted by: Lee at August 8th, 2020 9:39 AM

Importantly, aged HSCs treated with CASIN reestablished an immune system similar to that of young animals, and thus capable of mounting a strong immune response to vaccination.
https://doi.org/10.1182/blood-2018-02-831065
https://doi.org/10.1182/blood-2018-06-858696
However, an elevated dosage (20 μM) of CASIN killed all cells within 24 hours https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287229
Considering that the elderly make up only 15% of cases of COVID-19, but more than 95% of all deaths from it and do not respond well to vaccination, vaccine developers must before vaccinating the elderly, rejuvenate their immune systems.

Posted by: Dmitry Dzhagarov at August 9th, 2020 9:13 AM

You should be happy Dmitry, this is a ROCK-inhibitor!

Posted by: Mark at August 10th, 2020 3:23 AM

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