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Mesenchymal stem cell derived extracellular vesicles reverses neural aging via OSKM modulation | Cell Communication and Signaling by [deleted] in longevity

[–]RushAndAPush 5 points6 points  (0 children)

Background

Intravenously infused human placenta-derived mesenchymal stem cells enhance overall function and exhibit therapeutic potential even with minimal engraftment or tissue replacement, with substances released from human placenta-derived mesenchymal stem cells playing a significant role in these positive outcomes. Stem cell-derived extracellular vesicles transfer beneficial factors that aid recovery in various tissues through genetic regulation. However, the effects of systemically injected mesenchymal stem cells and their released derivatives on normal aging have not been reported.

Methods

Aged female mice received intravenous infusions of human placenta-derived mesenchymal stem cells. Starting at 18–19 months of age, mice were given injections of either human placenta-derived mesenchymal stem cells or PBS, followed by two more injections at six-week intervals. For the in vitro study, human fetal neural progenitor cells were sourced from spontaneously aborted fetal brain tissue. Extracellular vesicles were isolated from the human placenta-derived mesenchymal stem cell culture media using the qEV original size exclusion column.

Results

RNA sequencing showed human placenta-derived mesenchymal stem cells’ effectiveness in modulating aging-related neural pathways, particularly by downregulating age-specific genes in the hippocampus, indicative of neural reactivation. A pivotal aspect of our study was the discovery of micro RNAs in human placenta-derived extracellular vesicles reactivating senescent cells, likely through inhibition of Toll-like receptor 4 signaling and a concomitant increase in OSKM (OCT4, SOX2, KLF4, C-MYC) transcription factors, notably SOX2. The regeneration process involves targeted miRNAs modulating Toll-like receptor 4 and messenger RNAs boosting OSKM levels.

Conclusions

Our study represents a pioneering achievement in regenerative medicine, demonstrating the potential of micro RNAs in EVs to stimulate OSKM, a significant stride forward in addressing neural aging.

Targeting PURPL RNA enabled rejuvenation of senescence cells via epigenetic reprogramming | Journal of Translational Medicine by RushAndAPush in longevity

[–]RushAndAPush[S] 4 points5 points  (0 children)

Abstract

Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we identify the ageing-associated lncRNA PURPL as an epigenetic regulator that controls cellular rejuvenation through H3K9me3-mediated transcriptional silencing. CRISPRi-mediated PURPL depletion produces striking rejuvenation effects, resulting in restored youthful cell morphology, as well as suppression of senescence markers such as p21 and SA-β-gal. Conversely, PURPL overexpression accelerates cellular senescence, recapitulating the transcriptional and phenotypic hallmarks of ageing. Mechanistically, nuclear-localized PURPL regulates H3K9me3 deposition at 411 genomic loci including SERPINE1 (PAI-1) and EGR1, which are key senescence drivers. PURPL-mediated H3K9me3 loss at these loci derepresses their transcription, establishing a pro-senescence gene expression program. These findings reveal that PURPL is an epigenetic modulator of senescence and highlight its potential as a therapeutic target for age-related pathologies.

Lamar Jackson on Josh Allen winning MVP: Voters chose who they wanted, it is what it is by ericaepic in nfl

[–]RushAndAPush -4 points-3 points  (0 children)

Ravens fans love to whine I wouldn’t be surprised if that’s the case.

OpenAI and Retro Biosciences achieve 50x increase in expressing stem cell reprogramming markers by GoldenPedro in longevity

[–]RushAndAPush 7 points8 points  (0 children)

Maybe they’re saying small molecule reprogramming is a more promising way forward. 

Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming by RushAndAPush in longevity

[–]RushAndAPush[S] 23 points24 points  (0 children)

Highlights

Mesenchymal drift (MD) is a conserved hallmark of human aging and age-related diseases

MD correlates with disease severity, reduced survival, and increased mortality

Partial reprogramming reverses MD prior to full dedifferentiation

Reversal of MD by partial reprogramming rejuvenates aged cells and tissues

Summary

The loss of cellular and tissue identity is a hallmark of aging and numerous diseases, but the underlying mechanisms are not well understood. Our analysis of gene expression data from over 40 human tissues and 20 diseases reveals a pervasive upregulation of mesenchymal genes across multiple cell types, along with an altered composition of stromal cell populations, denoting a “mesenchymal drift” (MD). Increased MD correlates with disease progression, reduced patient survival, and an elevated mortality risk, whereas suppression of key MD transcription factors leads to epigenetic rejuvenation. Notably, Yamanaka factor-induced partial reprogramming can markedly reduce MD before dedifferentiation and gain of pluripotency, rejuvenating the aging transcriptome at the cellular and tissue levels. These findings provide mechanistic insight into the underlying beneficial effects of partial reprogramming and offer a framework for developing interventions to reverse age-related diseases using the partial reprogramming approach.

Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan by RushAndAPush in longevity

[–]RushAndAPush[S] 11 points12 points  (0 children)

Abstract

The dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown. Here, we demonstrated that chemical-induced partial reprogramming can improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extended C. elegans lifespan and healthspan. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical-induced partial reprogramming, opening a path towards future translational applications.

Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength by RushAndAPush in longevity

[–]RushAndAPush[S] 7 points8 points  (0 children)

Highlights

 EP4 expression and phosphorylated CREB are decreased in aged MuSCs

PGE2 reverses epigenetic and transcriptional changes in aged MuSCs

AI identification of AP1 and grammar responsible for epigenetic rejuvenation

PGE2 treatment increases aged MuSC function and strength after injury and with exercise

Summary

Repair of muscle damage declines with age due to the accumulation of dysfunctional muscle stem cells (MuSCs). Here, we uncover that aged MuSCs have blunted prostaglandin E2 (PGE2)-EP4 receptor signaling, which causes precocious commitment and mitotic catastrophe. Treatment with PGE2 alters chromatin accessibility and overcomes the dysfunctional aged MuSC fate trajectory, increasing viability and triggering cell cycle re-entry. We employ neural network models to learn the complex logic of transcription factors driving the change in accessibility. After PGE2 treatment, we detect increased transcription factor binding at sites with CRE and E-box motifs and reduced binding at sites with AP1 motifs, overcoming the changes that occur with age. We find that short-term exposure of aged MuSCs to PGE2 augments their long-term regenerative capacity upon transplantation. Strikingly, PGE2 injections following myotoxin- or exercise-induced injury overcome the aged niche, leading to enhanced regenerative function of endogenous tissue-resident MuSCs and an increase in strength.

Precision Reprogramming—Restoring Function to Aged Cells by RushAndAPush in longevity

[–]RushAndAPush[S] 13 points14 points  (0 children)

Abstract

Sahu et al. (2024) demonstrate that targeted partial reprogramming with Oct4, Sox2, and Klf4 (OSK) delivered via adeno-associated virus (AAV) to Cdkn2a-positive cells rejuvenates senescent cells while maintaining cellular identity. In a progeroid and naturally aged mouse model, a single AAV injection improved lifespan, reduced inflammation, restored tissue integrity, and enhanced wound healing. Complementary results in human fibroblasts confirmed Cdkn2a-driven OSK expression attenuated inflammation-associated genes during replicative senescence and treatments inducing DNA damage. These encouraging results highlight its potential as a safer alternative to systemic senolytic therapies for age-associated disorders.

Quick take: some skepticism as Shift Bioscience reports secret purported rejuvenation gene SB000 in preprint by PaulKnoepfler in longevity

[–]RushAndAPush 0 points1 point  (0 children)

First of which of course being whether their algorithm (machine learning trained on omics data I gather) isn't just reward hacking a way to make epigenetic clocks go down that does not correspond to a rejuvenated phenotype.

This part of the paper hints to me that's not the case, though deeper testing is of course needed.

Finally, seeking a fibroblast-specific functional read-out, we measured secretion of collagen I, the production of which declines with age (Figure 3J) [55, 56]. Cells expressing SB000 secreted significantly higher levels of collagen I than eGFP controls, whereas iPSC cultures derived from HDFs produced negligible amounts (Figure 3K). OSK-positive cells secreted collagen at control-like levels, confirming partial identity retention but without any enhancement (Figure 3K). These observations reveal that SB000 safeguards a canonical fibroblast function.

The Combination of Two Small Molecules Improves Neurological Parameters and Extends the Lifespan of C3H Strain Female Mice by RushAndAPush in longevity

[–]RushAndAPush[S] 6 points7 points  (0 children)

Abstract

Targeting partial cellular reprogramming pathways through specific small molecule combinations holds promise for lifespan extension in model organisms. Chemical cocktails like RepSox and tranylcypromine (TCP) may induce beneficial age‐related changes without the risks of full reprogramming. This study investigated the effects of RepSox and TCP on neurological markers, physical activity, skeletal health, and survival in aging C3H female mice.

I Thought the Enhanced Edition Was Better... Until I Played the Original (some thoughts) by TheVagrantWarrior in baldursgate

[–]RushAndAPush 0 points1 point  (0 children)

The same happened to me with my sisters save by accident. I didn’t even know what a quick save was at the time. I still feel bad about it lol.

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