LongeCityNews Last Updated: 17 February 2026 - 12:39 PM

The peptide industry has been growing for some years now, becoming more vocal and visible. It occupies a similar space to the supplement industry, and seems likely to provoke many of the same battles with regulators such as the FDA. Peptide use is characterized by the same lack of rigorous supporting data that attends supplement use, and for many of the same reasons. The lines in the sand dividing peptide from drug are just as arbitrary as those dividing supplement and drug, and just as driven by funding and the high cost of regulatory compliance. Peptides that can be effectively monopolized via intellectual property become drug candidates, as only with that monopoly is it possible to raise enough funding to engage with regulators and run clinical trials. Peptides that cannot remain on the outside, without the robust human data needed to support greater interest.

Against the background of this broader context of a growing market for the use of peptides, you might recall that the peptide FOXO4-DRI was one of the early potential senolytic therapies to be validated in animal studies, back in the mid-2010s. FOXO4-DRI interferes in the interaction between FOXO4 and p53 that normally inhibits apoptosis of senescent cells, and thus results in the selective destruction of senescent cells with very little impact on other cells. Clearance of senescent cells is well demonstrated to improve health in aged animal models, but only relatively small clinical trials of a few senolytic small molecules have yet taken place to validate use in humans.

A company, Cleara Biotech, was formed to commercialize the early academic work on FOXO4-DRI, and appears to still be a going preclinical concern focused more on the FOXO4-p53 interaction than on FOXO4-DRI per se. Other groups have since become involved, such as Numeric Biotech, and it has long been the case that anyone so minded can just up and buy FOXO4-DRI for personal use from any number of peptide sellers. It is unclear as how many people are choosing to do that, and certainly we'll never see any sort of useful data resulting from that use. Meanwhile, academic research groups continue to work with FOXO4-DRI as a tool to explore the FOXO4-p53 interaction in the context of cellular senescence as a driver of degenerative aging.

FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway

Endothelial cell dysfunction during aging is a key driver of vascular aging and related diseases; however, effective strategies to selectively eliminate senescent endothelial cells and restore vascular function remain lacking. FOXO4-DRI, a novel peptide-based intervention, specifically disrupts the interaction between FOXO4 and P53, thereby inducing apoptosis in senescent cells. This study innovatively focuses on the mechanism by which FOXO4-DRI induces apoptosis in senescent endothelial cells, demonstrating that it functions by activating the p53/BCL-2/Caspase-3 signaling pathway to promote selective apoptosis of these cells. FOXO4-DRI significantly improves vascular function and delays vascular aging.

This study aims to analyze the vascular function and aging status of the aorta in naturally aged mice and progeroid model mice following FOXO4-DRI injection. Additionally, it investigates changes in endothelial cell function in senescent endothelial cells induced by oxygen-glucose deprivation (OGD), as well as the protein expression and interaction in the FOXO4-P53 signaling pathway. To assess the impact of FOXO4-DRI on endothelial cell senescence, the senescent endothelial cells were treated with FOXO4-DRI, followed by immunofluorescence and Western blotting experiments.

Injection of FOXO4-DRI in both naturally aged and induced aging mice effectively suppressed aortic aging and improved aortic function. Additionally, we found that FOXO4-DRI alleviates endothelial cell senescence induced by OGD, thereby enhancing endothelial cell function. Through co-immunoprecipitation (CO-IP) experiments, we discovered that FOXO4-DRI prevents the binding of FOXO4 to P53, facilitating the phosphorylated P53 nuclear exclusion, which subsequently trigger BAX and cleaved caspase-3, leading to the apoptosis of senescent cells. Ultimately, this mechanism achieves the goal of inhibiting vascular aging.

Researchers have found that altering a growth hormone receptor in the brain adipose tissue of aged male mice slows their mental aging and allows them to perform far better on cognitive tests.

Growth signaling is not necessarily good

The axis of growth hormone and insulin-like growth factor 1 (IGF-1) is well-known in aging, and the relationship between this regulator and brain aging has been previously documented [1]. Interestingly, while circulating growth hormone and IGF-1 levels decline with aging [2], suppressing this signaling extends lifespan [3], and mice with reduced levels of this signaling perform better on cognitive tests [4]; this also occurs when the mice express an agonist that suppresses it [5].

The researchers of this study focused on its effects on fatty (adipose) tissue, which is metabolically active and secretes factors that affect other systems [6], including the brain [7]. While previous work has discovered that adipose-specific growth hormone knockout (Ad-GHRKO) mice have better insulin sensitivity and longer lives [8], how well these mice perform on cognitive tests had not been previously measured.

Benefits for neural function and inflammation

The researchers first directly examined the brains of these mice, comparing 18- to 24-month-old Ad-GHRKO mice to controls. The modified mice were more neurally active overall and had less neuronal loss in the dentate gyrus, the part of the hippocampus responsible for forming new memories. This was accompanied by an increase in synapse formation and a decrease in neuroinflammation: there were decreases in the inflammatory factors IL-6 and TNF-α along with an increase in the anti-inflammatory factor IL-10.

There was also a reduction in cellular senescence. The modified mice had significantly less of the senescence marker SA-β-gal throughout their brains, including the amyglada, the dentate gyrus, and the cortex. They also had significantly less tau phosphorylation, an age-related protein alteration that contributes to cognitive decline and, in humans, is a sign of Alzheimer’s disease.

The excitability of neurons declines with age, and here, too, knocking out growth hormone in the adipose tissue proved beneficial; the aged modified mice fired their neurons much more like younger mice did, while aged controls had stark reductions in neural firing frequency.

Stark benefits on cognitive tests

The researchers then turned to four standard cognitive tests: the novel object recognition test, which shows that the mice can discriminate between familiar and unfamiliar things; the Y-maze tests, which tests for exploration ability; the Morris water maze test, which tests memory and navigation behavior; and a floor shock test, which tests memory in adversive conditioning. On all four of these tests, the aged modified mice performed almost exactly like their younger counterparts, while the aged controls performed far worse; this was in spite of the modification not noticeably affecting the older mice’s physical ability.

According to the authors, “this study provides evidence that adipose tissue acts as a key peripheral regulator of brain aging.” While the number and power of cognitive and biochemical benefits that arose from this modification are striking, these experiments were performed on a single-sex group of genetically altered mice. Aapplying these findings to wild-type animals, and then human beings, is a challenge of its own.

Literature

[1] Ashpole, N. M., Sanders, J. E., Hodges, E. L., Yan, H., & Sonntag, W. E. (2015). Growth hormone, insulin-like growth factor-1 and the aging brain. Experimental gerontology, 68, 76-81.

[2] Liu, H., Bravata, D. M., Olkin, I., Nayak, S., Roberts, B., Garber, A. M., & Hoffman, A. R. (2007). Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Annals of internal medicine, 146(2), 104-115.

[3] Bartke, A. (2008). Growth hormone and aging: a challenging controversy. Clinical interventions in aging, 3(4), 659-665.

[4] Kinney-Forshee, B. A., Kinney, N. E., Steger, R. W., & Bartke, A. (2004). Could a deficiency in growth hormone signaling be beneficial to the aging brain?. Physiology & behavior, 80(5), 589-594.

[5] Basu, A., McFarlane, H. G., & Kopchick, J. J. (2017). Spatial learning and memory in male mice with altered growth hormone action. Hormones and Behavior, 93, 18-30.

[6] Booth, A., Magnuson, A., Fouts, J., & Foster, M. T. (2016). Adipose tissue: an endocrine organ playing a role in metabolic regulation. Hormone molecular biology and clinical investigation, 26(1), 25-42.

[7] Letra, L., & Santana, I. (2017). The influence of adipose tissue on brain development, cognition, and risk of neurodegenerative disorders. Obesity and Brain Function, 151-161.

[8] List, E. O., Berryman, D. E., Slyby, J., Duran-Ortiz, S., Funk, K., Bisset, E. S., … & Kopchick, J. J. (2022). Disruption of growth hormone receptor in adipocytes improves insulin sensitivity and lifespan in mice. Endocrinology, 163(10), bqac129.

There are so many detrimental age-related changes in gene expression that it will always be possible to pick out any one gene exhibiting altered expression and spend years on research and development aimed at fixing this one specific issue. Restoring youthful expression of any one gene in any one tissue is an achievable goal for present day medical research and development, though costs and regulatory hurdles remain challenging. Expression can be increased via gene therapy vectors, or reduced via various approaches, such as small interfering RNA, that attack some part of the process of gene expression. The most productive future will not be one of picking through thousands of changes one by one, however, but instead a matter of attempts to restore youthful gene expression more generally, for most or all genes, through some form of reprogramming. Still, the one by one approach remains the primary focus of the research community, as this example illustrates, though at least researchers now tend to favor regulatory genes that influence the expression of large numbers of other genes.

O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis.

While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.

Link: https://doi.org/10.1002/cbic.202500774

Researchers here provide evidence for glycogen produced by the gut microbiome to contribute to age-related neurodegeneration. A mutation associated with amyotrophic lateral sclerosis and frontotemporal dementia appears to make the inflammatory consequences of microbiome-derived glycogen worse, thus potentially explaining its relevance to disease. But the prevalence of the microbes involved in the production of glycogen in the gut microbiome of patients with these conditions suggests that every older person is impacted by this mechanism to some degree, with that degree being dependent on the exact composition of the gut microbiome. This is one of a range of studies showing at least some correlation between gut microbiome composition and specific age-related conditions, and as illustrated here, researchers are starting to move beyond correlation to explore the mechanisms responsible.

Gut dysbiosis and neural inflammation occur in patients with amyotrophic lateral sclerosis (ALS), including those with a causal mutation in chromosome 9 open reading frame 72 (C9ORF72). How gut commensals interact with common ALS genotypes to impart risk of neural degeneration remains unclear. Here, we identify 10 phylogenetically diverse bacterial strains that promote cytokine release in a C9orf72-dependent manner. Metatranscriptomics implicated the glycogen biosynthesis pathway as a driver of inflammation.

Colonization of germ-free C9orf72-deficient mice with Parabacteroides merdae that produced inflammatory glycogen enhanced monocytosis, blood-brain barrier breakdown, and T cell infiltration into the central nervous system. Enzymatic digestion of glycogen in the gut promoted survival of C9orf72-deficient mice and dampened microglial reactivity in the brain.

A survey of human fecal samples demonstrated that inflammatory forms of glycogen were present in gut contents from 15/22 patients with ALS, 1/1 patient with C9ORF72 frontotemporal dementia (FTD), and 4/12 healthy controls. Together, the results of this work identify bacterial glycogen as a modifiable mediator of immune homeostasis in the gut and brain.

Link: https://doi.org/10.1016/j.celrep.2025.116906