A number of variants of the FOXO3 gene are associated with greater longevity, which researchers believe may be due to an altered distribution of different forms of the FOXO3 protein. Here, researchers note a study in which a human pluripotent cell line was engineered with a favorably altered FOXO3 sequence and differentiated into mesenchymal progenitor cells. These cells were injected into aged monkeys, producing an across the board improvement in measures of health and function. This is much as one would expect from a good stem cell therapy repeated over time, but it is unclear as to whether the mechanisms involved go beyond a suppression of age-related chronic inflammation. Generally, transplanted cells die quickly. Beneficial effects are derived from the signals that they produce, favorably altering the behavior of native cells for a time. The most reliable outcome is reduced inflammation.
FOXO3 is a well-established regulator of longevity, stress resistance, and stem-cell maintenance. In a pioneering effort to reprogram aging-related genetic circuits, researchers introduced two phospho-null mutations (S253A and S315A) to eliminate phosphorylation sites into the FOXO3 locus, generating engineered human embryonic stem cells that, upon mesenchymal differentiation, gave rise to progenitor cells with enhanced stress resilience and self-renewal capacity – designated as senescence-resistant cells (SRCs).
Administering SRCs intravenously to aged cynomolgus monkeys over a 44-week period led to a cascade of restorative changes. Compared to wild-type mesenchymal cells, SRCs more effectively reversed age-related changes across the brain, immune system, bone, skin, and reproductive tissues. Multi-modal assessments-behavioral, histological, transcriptomic, and methylomic-consistently indicated biological age reversal.
Notably, SRC-treated monkeys exhibited improved cognitive function, restored cortical architecture, and enhanced hippocampal connectivity. Bone density increased, periodontal degeneration was mitigated, and immune cell transcriptional profiles shifted toward a youthful state. At the molecular level, transcriptomic aging clocks showed an average reversal of 3.34 years with SRCs, while DNA methylation clocks corroborated these effects in multiple tissues. Furthermore, the authors observed the restoration of reproductive system health. In both male and female monkeys, SRC treatment reduced senescent markers, enhanced germ cell preservation, and reversed transcriptional aging clock across ovaries and testes. Single-cell transcriptomics revealed that oocytes, granulosa cells, and testicular germ cells responded particularly well, rejuvenating by up to 5-6 years.
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