Senescence/Regeneration/Aging

  • The activation of redox-sensitive transcription factor Nrf2 1) curbs oxidative damage, 2) preserves vital immune functions (including inflammatory migration), 3) delays the acquisition of senescence-like features.
  • Macrophage Nrf2 also acts non-autonomously to limit ROS-induced collateral damage to surrounding tissues
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  • Microglia are not necessary for the initial process of myelin ensheathment during development.
  • However, microglia play a crucial role in regulating myelin growth and associated cognitive function after development.
  • Microglia are also responsible for maintaining myelin integrity and preventing its degeneration.
  • The absence of microglia leads to the emergence of a myelinating oligodendrocyte state with altered lipid metabolism, contributing to the loss of myelin health.
  • This mechanism is regulated through the disruption of the TGFβ1-TGFβR1 axis.
  • Targeting microglia could be a potential therapeutic approach for conditions characterized by dysregulated myelin growth and integrity, such as ageing and neurodegenerative diseases.
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Cell Secretome vs Stem Cells

  • Stem cell-based therapies were initially explored for tissue regeneration and immunomodulation.
  • Engraftment and differentiation of stem cells were thought to be the main mechanisms.
  • However, poor homing and engraftment of systemically and topically applied stem cells, leading to a search for alternative mechanisms of action
  • Non-stem cells, particularly autologous activated blood mononuclear cells, showed improvement in wound healing.
  • Stem cells release cytoprotective, trophic, and immunomodulatory paracrine factors. The sum of these factors is termed the cell secretome, which has become a major focus of recent studies.
  • Proteins, lipids, and extracellular vesicles (EVs) are the major fractions of cell secretomes.
  • EVs, including exosomes and microvesicles, are extensively researched and mediate bioactive properties through membrane interactions and cargo delivery.
  • The scope of potential indications for secretome-based therapeutics extends the treatment of chronic wounds because the tissue-regenerative properties of these candidates have been documented in almost all organ systems (Beer et al., 2016;Moghadasi et al., 2021

https://www.jidonline.org/article/S0022-202X(23)00162-8/fulltext

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Cellular senescence has typically been associated with negative effects, but in a new study, it is shown to enhance newt limb regeneration.

  1. Salamanders can regenerate their entire limbs throughout their lifespan.
  2. Limb regeneration involves significant modulation of cellular plasticity.
  3. The process of limb regeneration induces cellular senescence, which is irreversible cell cycle arrest.
  4. Exogenously derived senescent cells promote dedifferentiation of mature muscle tissue that generates regenerative progenitors.
  5. Senescent cells promote myotube cell cycle re-entry and reversal of muscle identity through secreted factors.
  6. The FGF-ERK signaling axis is identified as a critical mediator of senescence-induced muscle dedifferentiation.
  7. Cellular senescence plays a beneficial role as a modulator of dedifferentiation, which is crucial for the regeneration of complex structures.

https://onlinelibrary.wiley.com/doi/10.1111/acel.13826

  1. Niche signals and stem cell maintenance:
  • Niche signals have two roles: maintaining stem cells in prolonged quiescence or transiently activating them for proper regeneration.
  • Altering balanced niche signaling can result in regenerative disorders.
  1. Relationship between melanocytic skin nevi and hair growth:
  • Melanocytic skin nevi in humans often exhibit excessive hair growth, suggesting hair stem cell hyperactivity.
  1. Study using genetic mouse models of nevi:
  • Dermal clusters of senescent melanocytes in nevi induce changes in epithelial hair stem cells.
  • Senescent melanocytes drive hair stem cells to exit quiescence and alter their transcriptome and composition.
  • These changes significantly enhance hair renewal.
  1. Identification of nevus secretome and its role in hair growth:
  • Nevus melanocytes activate a distinct secretome enriched with signaling factors.
  • Osteopontin, a prominent signaling factor in nevi, plays a crucial role in inducing hair growth.
  • Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice.
  • Germline and conditional deletions of osteopontin or its receptor CD44 prevent enhanced hair growth induced by dermal nevus melanocytes.
  • Osteopontin is overexpressed in human hairy nevi and stimulates new growth of human hair follicles.
  1. Senescent cell clusters as a therapeutic target in regenerative disorders:
  • Accumulation of senescent cells generally hampers tissue regeneration.
  • However, the study reveals that senescent cell clusters and their secretome can enhance adjacent intact stem cell activity and stimulate tissue renewal.
  • This finding highlights senescent cells and their secretome as potential therapeutic targets in regenerative disorders.

Signalling by senescent melanocytes hyperactivates hair growth | Nature

New study:

  1. Senescent cells as mediators of cellular plasticity: The study reveals that senescent cells emit signals that can destabilize neighboring somatic cells, leading to their reprogramming into stem cells. This reprogramming plays a pivotal role in driving whole-body regeneration in the cnidarian Hydractinia symbiolongicarpus.
  2. Prevention of reprogramming and regeneration through inhibition of senescence: The researchers found that inhibiting senescence, either through pharmacological or genetic means, prevents the reprogramming of somatic cells and hinders the process of regeneration.
  3. Induction of senescence for enhanced regeneration: Interestingly, the induction of transient ectopic senescence in a regenerative context resulted in the formation of extra stem cells and accelerated the regeneration process. This suggests that senescence signaling can be manipulated to promote cellular plasticity and enhance regeneration.
  4. Implications for understanding ancient mechanisms of cellular plasticity: The study proposes that senescence signaling is an ancient mechanism that mediates cellular plasticity. By gaining a deeper understanding of the senescence environment that promotes cellular reprogramming, researchers may uncover new strategies to enhance regeneration in complex animals.
  1. Genetically immortalized bovine satellite cells (iBSCs) achieved over 120 doublings at the time of publication.
  2. The goal is to produce millions of metric tons of biomass annually through in vitro expansion of muscle cells from food-relevant species.
  3. Genetically immortalized cells offer rapid growth and escape from cellular senescence.
  4. The development involves constitutive expression of bovine Telomerase reverse transcriptase (TERT) and Cyclin-dependent kinase 4 (CDK4) in iBSCs.
  5. The genetically immortalized cells maintain their capacity for myogenic differentiation.

Immortalized Bovine Satellite Cells for Cultured Meat Applications | ACS Synthetic Biology

Pharmacological YAP activation promotes regenerative repair of cutaneous wounds

  1. Life Expectancy Impact: Chronic cutaneous wounds are associated with a decrease in life expectancy.
  2. Quality of Life Impact: Chronic cutaneous wounds also negatively affect the quality of life of affected individuals.
  3. Efficacy in Animal Models: The topical application of PY-60, a small-molecule activator of YAP, promoted regenerative repair of cutaneous wounds in pig models.
  4. Efficacy in Human Models: The topical application of PY-60 also promoted regenerative repair of cutaneous wounds in human models.
  5. Proliferative Transcriptional Program: Pharmacological YAP activation induces a reversible pro-proliferative transcriptional program in keratinocytes and dermal cells.
  6. Accelerated Healing: The pro-proliferative transcriptional program results in accelerated re-epithelization and regranulation of the wound bed.
  7. Generalizable Therapeutic Approach: Transient topical administration of a YAP activating agent shows potential as a generalizable therapeutic approach for treating cutaneous wounds.

https://www.pnas.org/doi/full/10.1073/pnas.2305085120

  1. MBTD1 is highly expressed in fetal hematopoietic stem cells (HSCs).
  2. Numbers of HSCs and progenitors increase in Mbtd1-deficient hematopoietic tissues.
  3. Mbtd1-deficient HSCs exhibit hyperactive cell cycle.
  4. MBTD1 directly binds to the promoter region of FoxO3a.
  5. FOXO3a is a forkhead protein essential for HSC quiescence.
  6. MBTD1 interacts with components of the TIP60 chromatin remodeling complex.
  7. MBTD1 interacts with proteins involved in HSC and other stem cell functions.
  8. Restoration of FOXO3a activity in Mbtd1-deficient HSCs rescued cell cycle and pool size abnormalities.
  1. A study assessed the impact of aging on the cardiac neurovascular interface, where nerves align with blood vessels.
  2. Aging leads to a reduction in nerve density within the ventricle of the heart.
  3. Aging also dysregulates genes related to neuroregulation derived from blood vessels.
  4. The aging process down-regulates microRNA 145 (miR-145) and leads to the derepression of the neurorepulsive factor semaphorin-3A (Sema3A).
  5. Deletion of miR-145 or overexpression of endothelial Sema3A reduces axon density, mimicking the phenotype of an aged heart.
  6. Senescent cells accumulate with age and are associated with a decline in nerve density in the heart.
  7. Removing senescent cells rescues age-induced denervation, reverses Sema3A expression, preserves heart rate patterns, and reduces electrical instability.
  8. These findings suggest that senescence-mediated regulation of nerve density plays a role in age-associated cardiac dysfunction.
  1. The periodontium, a complex structure, is composed of interconnected soft and mineralized tissues.
  2. Silicon and lithium stimulate bone repair via silicic acid release and activate the Wnt/β-catenin pathway.
  3. Existing materials for combined lithium and silicon release have limited control over ion release amounts and kinetics.
  4. Porous silicon provides controlled silicic acid release, inducing osteogenesis for bone regeneration.
    Prelithiation, a strategy for battery technology, introduces controllable amounts of lithium within porous silicon.
  5. The study introduces lithiated porous silicon nanowires (LipSiNs) as a biocompatible and bioresorbable material.
  6. LipSiNs incorporate lithium to between 1% and 40% of silicon content.
  7. LipSiNs release lithium and silicic acid in a tailorable fashion from days to weeks.
  8. LipSiNs combine osteogenic, cementogenic, and Wnt/β-catenin stimuli to regenerate bone, cementum, and periodontal ligament fibers in a murine periodontal defect.
  1. Gut and liver communication occurs through various pathways: biliary tract, portal vein, and systemic circulation.
  2. Liver-derived pigment epithelium-derived factor (PEDF) regulates intestinal stem cell (ISC) hyperproliferation.
  3. PEDF acts as a soluble Wnt inhibitor, restraining the Wnt/β-catenin signaling pathway to maintain gut homeostasis.
  4. Intestinal inflammation triggers microbial danger signals sensed by the liver, leading to repression of PEDF production via peroxisome proliferator-activated receptor-α (PPARα).
  5. Repression of PEDF liberates ISC proliferation, accelerating gut tissue repair.
  6. Treatment with fenofibrate, a PPARα agonist, enhances colitis susceptibility due to increased PEDF activity.
  1. Accumulation of senescent cells in tissues contributes to aging and age-related diseases.
  2. Botanical extracts, rich in phytoconstituents, are potential sources for therapies targeting senescence to improve healthspan.
  3. Daily oral administration of a standardized extract of Salvia haenkei (Haenkenium, HK) extended both lifespan and healthspan in naturally aged mice.
  4. HK treatment inhibited age-induced inflammation, fibrosis, and senescence markers across various tissues and increased muscle strength and fur thickness.
  5. HK treatment also reduced acutely induced senescence by the chemotherapeutic agent doxorubicin, as observed in p16LUC reporter mice.
  6. Mass spectrometry identified luteolin as the most concentrated flavonoid in HK, acting as a senomorphic compound.
  7. Luteolin was found to disrupt the p16–CDK6 interaction, which may underlie the longevity-promoting effects of HK.
  8. The study demonstrates that HK promotes longevity in mice, potentially by modulating cellular senescence and disrupting the p16–CDK6 interaction.

Targeting senescence induced by age or chemotherapy with a polyphenol-rich natural extract improves longevity and healthspan in mice | Nature Aging

  1. mRNA would be degraded prematurely without molecular caps protecting the two mRNA ends, for instance, the 3’ end mRNA is equipped with a polyadenine tail with an average length of 200 nucleotides. But even this shield does not last long as deadenylation occurs – the average half-life of mRNA is only 7 hours.
  2. Deadenylation is a process that the target mRNA is recruited by RNA-binding proteins to the protein complex CCR4-NOT, which removes one adenine after the other.
  3. The subunit NOT9 binds various RNA binding proteins which recruit mRNA in a sequence-specific manner to the CCR4-NOT complex to promote their deadenylation.
  4. the hydrocarbon stapled peptide NIP-2 (KD = 60.4 nM) was able to inhibit RNA-binding (IC 50 = 333nM) as well as the deadenylation activity of the CCR4-NOT complex in vitro while being cell-permeable (EC 50 = 2.44 μM).
  5. NIP-2 bound to NOT9 allowed further optimization of thepeptide through point mutation leading to NIP-2-H27A-N 3 (KD = 122nM) with high cell permeability (cell-permeability EC 50 = 0.34 μM).
  6. The optimized peptide was able to inhibit deadenylation of target mRNAs when used in HeLa cells at a concentration of 100 μM demonstrating the feasibility of increasing mRNA stability.
  7. This new strategy provides us to extend the lifespan of mRNA by protecting it from its dismantling.

ARTICLE: Stapled Peptides as Inhibitors of mRNA Deadenylation
https://onlinelibrary.wiley.com/doi/epdf/10.1002/anie.202413911

  • Calorie restriction (CR) is a potential intervention to slow aging.
  • CR reduced circulating biomarkers of cellular senescence.
  • CR improved metabolic health, as indicated by changes in HOMA-IR and insulin sensitivity.
  • CR reduced senescence-related gene expression in adipose tissue.

Aging Cell 2024 Feb;23(2):e14038. doi: 10.1111/acel.14038. Epub 2023 Nov 14.

Synthetic peptides, combined with patient blood, can revolutionize personalized regenerative medicine by mimicking the body’s natural healing process.

Biocooperative Regenerative Materials by Harnessing Blood‐Clotting and Peptide Self‐Assembly - Padilla‐Lopategui - Advanced Materials - Wiley Online Library