A recent preprint study suggests that a NOVOS supplement can improve healthspan and extend lifespan in male mice [1].
Multiple ingredients, one goal
This preprint’s authors start by discussing dietary supplements’ beneficial effects on lifespan and markers of healthspan in multiple organisms and their possible additive and synergistic effects that result from targeting multiple aging mechanisms.
They also point to the anti-aging potential of drugs that ablate senescent cells (senolytics) and their recent research on the role of mitochondria in senescence and how mitochondrial uncouplers (e.g., BAM15) can be used in combination with senolytics such as navitoclax in order to increase their activity.
In this paper, they compare the NOVOS multi-ingredient dietary supplement and the senolytic BAM15/navitoclax treatment and their impact on the lifespan and healthspan of aged mice.
NOVOS is a formulation created by NOVOS, a New York-based company. It is a mix of 12 ingredients: pterostilbene, a resveratrol-related polyphenol derived from blueberries; glucosamine sulfate, a supplement used for osteoarthritis treatment; fisetin, a senotherapeutic; glycine, an amino acid; lithium aspartate, a mineral; calcium alpha-ketoglutarate, a small molecule naturally present in the human body; magnesium malate, a natural substance found in apples; vitamin C, also known as ascorbic acid; L-theanine, an amino acid found primarily in green and black tea; hyaluronic acid; Rhodiola rosea root extract; ginger root extract; and a boost consisting of β-nicotinamide mononucleotide (NMN).
We have recently reported on the effects of NOVOS on reducing DNA damage and oxidative stress in human skin cells in cultures.
Lifespan increase, but only tested in males
The researchers used 20 male mice in the experiments that were divided into three groups: control ©, dietary supplement (DS), and senolytic (SEN).
They started the treatments when the animals reached an older age (20 months). The DS animals received the soaked food with supplement mix daily until they died. The SEN group received Navitoclax and BAM 15 for five consecutive days in months 20 and 23. Mice were followed up until they died or until they reached 896 days (30 months), when the follow-up was terminated.
Both of the treatments resulted in significantly increased survival. The authors report that median survival in both treatment groups was higher by around 20% compared to controls: 830 days in the DS group, 834 days in the SEN group, and 703 days in the control group.
The authors also observed increased body weight. Before the first assessment at 21 months, it was noted that almost all mice had increased body weight. The authors attribute it to the increased food intake caused by the switch to the soaked food.
A month after the start of the treatment, body weight stagnated or decreased in the control group. However, the researchers observed continuous body mass increase in most animals until 27 months of age in the treated mice, both SEN and DS groups. They note that previous research has shown that body mass retention at older age can be used as a predictor of survival in mice.
While the results look encouraging, there are some caveats. The researchers note that the lifespan in the control group in this study was shorter compared to the same mouse strain used in the previous study [2].
They compared the studies to find factors that can be driving those differences. They propose two explanations: diet/body weight and possible infections.
First, they note that mice in this study received soaked food from 18 months old, which resulted in higher food intake and weight increases compared to mice fed standard food pellets. While they discussed that increasing body weight can benefit older mice, too much weight can lead to obesity and health complications. They suggest that tilting this balance to a less healthy phenotype could impact the mice’s lifespan.
Second, the researchers used intraperitoneal injections, directly into the body cavity, to administer BAM15. They suspect that this caused a wave of deaths in all three groups following the treatment (mice that didn’t receive BAM15 still had injections but without BAM15 to keep all the conditions the same). The postmortem examination of the animals suggests that mice died due to infection that resulted from these injections.
The authors reanalyzed the data in a way that censored those deaths. In this analysis, the median lifespan of the controls was longer (808 days), comparable to that of the previous study. In such cases, the lifespan of DS and SEN group animals was found to still be longer than the control, but only by around 10%.
Frailty and cognition
Apart from lifespan, the researchers also measured healthspan, specifically mice’s frailty, and noticed that both treatments reduced the frailty progression, but they differed in the pattern that depended on the timing of the treatment administration.
Since the NOVOS supplement was administered continuously, the researchers observed frailty diminishing with ongoing time, “almost reaching statistical significance at the 30 months assessment compared with controls.”
The senolytic treatment was administered twice, and the researchers observed the highest improvement in frailty assessment after the second round of treatment. However, it decreased in the next three months. This suggests that it would be worth testing if more rounds of senolytics treatment could prevent the decrease in frailty and whether, in such a setup, the results would be better for senolytic treatment or NOVOS supplementation.
The researchers also observed that short-term memory was sustained in the DS group during both assessments and in the second round of assessment in the SEN group, while the short-term memory of the control mice declined.
Senostatic but not senolytic
The authors wished to understand the mechanisms behind their observations. They used human fibroblasts to test not only the NOVOS supplement but each of its components separately to better understand which of the components is responsible for the observations.
Despite testing different concentrations, they did not observe a “preferential reduction of senescent over non-senescent fibroblast viability,” suggesting a lack of senolytic effect. However, when ethanol was used to dissolve the ingredients (as opposed to water), the researchers observed that a complete supplement decreases senescent cell size.
This change in cell size can be an indicator of senostatic activity. Senolytics eliminate senescent cells, while senostatics do not kill them but modulate the SASP.
The authors note that using ethanol and not water impacts the solubility of fisetin, as it is much less water-soluble. When Fisetin was tested alone, they observed effects on senescent cell size but not any senolytic effect. The authors also note that even though they didn’t observe a senolytic effect in these specific cells, it doesn’t mean the supplement doesn’t have such an effect in different cells. However, this remains to be formally tested.
Promising, but needs to be optimized
This promising effect is evident even when started relatively late in life. If such results could be translated into humans in the future, it would suggest that even late-life intervention would be beneficial. As the authors agree, there is still a need to optimize the treatment, and future studies should address that.
This lifespan and healthspan extension experiment has another major flaw. It was conducted only on male mice. The authors mention that this limitation was caused due to funding restrictions. However, their conclusions can still only be applied to male mice.
There are more and more reports on sex-dependent differences in different interventions. Conducting studies solely on one sex of animals might miss those sex-dependent differences. Additionally, female-specific aging is understudied, so excluding female mice from experiments adds to this gender inequality in medical research.
There are some conflicts of interest. One of the study authors is an employee of NOVOS Labs. Additionally, two authors are “named inventors on a patent describing the combination of BH3 mimetics and mitochondrial uncouplers as senolytics (WO2022053800A1).” NOVOS Labs also made a donation to one of the authors. However, the authors state that “the funders had no role in study design, collection, analysis and interpretation of data; writing of the report and decision to submit the article for publication.”
Disclosure: A portion of the profits and equity from NOVOS are being donated to nonprofits working in the longevity science space, which includes us here at Lifespan.io.
Our Vice President, Dr. Oliver Medvedik, is also a scientific consultant, putting him in good company with Dr. João Pedro de Magalhães, Dr. Pamela Maher, Dr. Avi Rosenbaum, and Dr. Matt Kaeberlein, names with whom regular readers may be familiar.
Literature
[1] Brookes, C., Fielder, E., Low, E., Barardo, D., von Zglinicki,T., Miwa, S.Comparable anti-ageing efficacies of a multi-ingredient nutraceutical and a senolytic intervention in old mice. bioRxiv 2024.10.11.617853
[2] Cameron, K. M., Miwa, S., Walker, C. & von Zglinicki, T. Male mice retain a metabolic memory of improved glucose tolerance induced during adult onset, short-term dietary restriction. Longev Healthspan 1, 3 (2012).
