The researchers of a recent study published in Aging Cell described their novel CD38 peptide vaccine, which improved many measurements of physical health and prevented cognitive decline in aged mice [1].
A long-term anti-aging vaccine
Many anti-aging strategies, such as supplementation, require regular, daily intake. A vaccine, on the other hand, is a therapeutic approach that, once administered, can have lasting effects.
Anti-aging vaccination approaches have already been undertaken previously, and they were designed to target, among others, senescent T cells and the cells that line blood vessels (vascular endothelial cells) [2, 3]. These researchers chose a different target: the widely researched CD38 protein expressed in several types of immune cells and tissues, which has multifunctional enzymatic activities related to NAD metabolism.
The age-dependent increase in CD38 levels has been linked to NAD+ decline and mitochondrial dysfunction [4]. Previous research on targeting CD38 with small molecules for therapeutic purposes showed benefits in glucose intolerance, physical dysfunction, and neuroinflammation [5, 6], while CD38 antibody research showed benefits against age-related syndromes, such as fibrosis, NAD+ deficiency, and cardiotoxicity [7-9], making it a promising target for a vaccine.
First, the researchers needed to find which part of CD38 would induce the strongest response from the immune system, thus making it the best candidate for a vaccine. While the researchers encourage future studies to test different sequences, they limited themselves to three amino acid sequences with which to create three peptide vaccines. After a few weeks, they tested how the immune systems of mice responded to the vaccines and chose the one that spurred the strongest response.
Physically stronger and cognitively younger
The researchers immunized a group of 12-month-old mice with the chosen vaccine. At 15-18 months old, the researchers analyzed the mice’s healthspan, then immunized them again at 18 months and 3 weeks of age and euthanized them at 20 months to collect tissues for further assessment.
The mice showed a strong immune response to the vaccination, translating into physical and cognitive health improvements in aged mice. The researchers observed that vaccination prevented a decline in total walking distance, maximal walking speed, grip strength, and hanging endurance in both male and female animals. Similarly, measuring physical fitness by placing mice in an open arena and observing their behavior showed better measures of total movement distance and average exploring velocity. Aged vaccinated mice also scored better on frailty scores and generally appeared younger than controls.
Cognitive skills were tested using a classic Morris water maze experiment and a novel object recognition model. The results suggested that the CD38 vaccine prevented cognitive decline in mice.
Beyond physical and cognitive tests, the researchers noted that vaccination improves metabolic features, which tend to deteriorate with age. They reported improvements in glucose tolerance, insulin sensitivity, and different measures of body energy consumption, such as energy expenditure and oxygen consumption, in aged mice compared to controls.
Decreasing senescence
These results prompted the researchers to investigate the underlying molecular mechanisms. Therefore, they analyzed both gene expression and the full suite of liver proteins (the proteome). This focus on the liver stems from its essential role in metabolism, including glucose and NAD+ metabolism, and its role as a target for anti-aging therapeutics, such as metformin and NAD+ precursors [10, 11].
First, the researchers confirmed that the vaccine specifically targeted CD38. Both gene expression and proteome analysis confirmed reduced CD38 levels.
Among the aging-related processes impacted by CD38 was senescence, and CD38 vaccination led to decreased senescence in aged mice’s solid organs. The researchers observed a decrease of the senescence marker p21 but not p16 in the liver along with decreased senescence-associated secretory phenotype (SASP) factors. Similarly, the activity of another senescence marker, SA-β-gal, was reduced in the liver and spleen following vaccination.
In previous experiments, the researchers reported CD38 vaccination’s impact on metabolic processes. This was also reflected at the molecular level.
In the liver, there was decreased expression of some glucose metabolism-related genes, specifically key glycolytic enzyme genes, in vaccinated animals compared to controls, which was confirmed by the proteome analysis. The proteome analysis also identified upregulation of fatty acid metabolic processes, breakdown of complex molecules (catabolism), and peroxisome proliferator-activated receptor (PPAR) signaling pathways, which, among other roles, regulate metabolic processes and are closely associated with oxidative phosphorylation (OXPHOS), which generates most cellular energy.
Reversing the decline
Previous research linked a specific group of immune cells, CD38-expressing macrophages, to age-related NAD+ decline [12]. NAD+ metabolism is an important player in aging. Anti-aging approaches aimed at NAD+ repletion have shown some beneficial anti-aging and healthspan-improving results.
In this study, vaccination reduced the levels of CD38-expressing macrophages in the liver and increased the NAD+/NADH ratio in the aged mice’s liver and brain tissue, partly restoring the age-related NAD+ decline.
In total, these results suggest ‘that the CD38 peptide vaccine ameliorated abnormal metabolism-related proteome shifts’ and rejuvenated the protein profile.
Proof of concept
This proof-of-concept study showed the anti-aging potential of the CD38 vaccine. The observed promising effects are most likely caused by the elimination of CD38-positive cells; however, different yet unidentified mechanisms may exist.
Since this research was conducted on mice, further studies are necessary to confirm its effect in people. The researchers also speculate that future studies should address its potential in different age-associated diseases, such as Alzheimer’s disease.
Peptide vaccines generally have high specificity and safety. Based on these results, this vaccine was not an exception from the rule, as the researchers did not detect any side effecs in the vaccinated mice. However, since CD38 plays a role in infection response, it might lead to increased infection rates, so researchers should monitor for possible infections in future studies.
Additionally, the activation of inflammatory responses might cause side effects. Inflammation is linked to aging and is thought to drive senescence, and in the short term, activation of inflammation might accelerate aging processes. Indeed, the researchers observed increased IL-6, one of the SASP factors, following vaccination in middle-aged and older mice, but it decreased later. These changes in inflammatory response warrant further investigation into how this CD38 vaccine impacts the immune system.
Literature
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