Peptide Sciences Blog

The aging process is strongly associated with developing diseases, such as cardiovascular conditions, hypertension, cancer, diabetes mellitus, osteoporosis, and neurodegenerative diseases, among others. ^[10,12] Alzheimer's disease (AD) is no exception since aging is a risk factor for late-onset AD (more than 95% of AD cases). ^[14,15] Another factor highly associated with aging is the increased cellular senescence population of different cell types as we approach older ages (see Fig. 3).^[14] Several studies suggest cellular senescence is critical in aging and connected conditions like AD.^[2,5,10] Recent investigations have pointed out that senescent cells promote the pathogenesis of AD.^[3-6] But what are senescent cells? Senescent cells' particular feature is stopping the proliferation by entering a cell cycle arrest. ^[12-15] these senescent cells are also known to develop apoptosis resistance and secrete proinflammatory molecules.^[11] Senescent cells not only remain even though they are "damaged" but also liberate various chemicals that can initiate inflammation.^[3,7] Cellular senescence emerges when a cell receives considerable stress, driving it to "reprogram" its fate to an unlimited cell cycle arrest.^[7,9] DNA damage, oncogene triggering, mitochondrial dysfunction, and the accumulation of proteins like the tau and the amyloid beta (Aβ) are well known to initiate senescence in different types of cells (see Fig. 1).^[2,12,14]

Figure 1. The comparison between a healthy brain and an AD brain with senescent cells.^[14]

Stem cells are undifferentiated cells that have the potential to differentiate into different cell types and regenerate tissues. They are essential for tissue homeostasis, repair, and regeneration throughout the body. Stem cells are characterized by their ability to self-renew and differentiate into various cell types, including muscle, nerve, and blood cells, among others.

Stem cell exhaustion is a state in which the body's stem cells become depleted, leading to impaired tissue regeneration and increased susceptibility to age-related diseases. As we age, the number and function of stem cells decline, leading to a decreased ability to repair and regenerate tissues. Stem cell exhaustion can result from a combination of factors, including oxidative stress, inflammation, and telomere shortening.

Oxidative stress, which occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defense mechanisms, can lead to stem cell damage and impaired function. Chronic inflammation, which is common in aging, can also lead to stem cell exhaustion, as the immune response can damage stem cells and their microenvironment. Telomere shortening, which occurs naturally as cells divide, can also limit the lifespan of stem cells, and contribute to stem cell exhaustion.

Stem cell exhaustion can have several harmful effects on the body. Firstly, it can impair tissue repair and regeneration, leading to a decreased ability to recover from injury or disease. Secondly, stem cell exhaustion can lead to the accumulation of damaged cells and tissues, which can contribute to age-related diseases such as cancer. Thirdly, stem cell exhaustion can impair the immune system's ability to fight infections and diseases.

There are several strategies to prevent or delay stem cell exhaustion, including maintaining a healthy lifestyle, such as a balanced diet and regular physical activity, reducing oxidative stress and inflammation, and promoting stem cell activation and proliferation through targeted therapies. Additionally, stem cell transplantation and regenerative medicine approaches may also help to replenish the body's stem cell pool and improve tissue regeneration.

Stem cell exhaustion is a state in which the body's stem cells become depleted, leading to impaired tissue regeneration and increased susceptibility to age-related diseases. Stem cell exhaustion can result from a combination of factors, including oxidative stress, inflammation, and telomere shortening. Stem cell exhaustion can impair tissue repair and regeneration, contribute to age-related diseases such as cancer, and weaken the immune system. Strategies to prevent or delay stem cell exhaustion include maintaining a healthy lifestyle, reducing oxidative stress and inflammation, and promoting stem cell activation and proliferation

“In this study, we explored the effect of FOXO4-DRI on bleomycin (BLM)-induced PF mouse model. We found that similar as the approved medication Pirfenidone, FOXO4-DRI decreased senescent cells, downregulated the expression of senescence-associated secretory phenotype (SASP) and attenuated BLM-induced morphological changes and collagen deposition. Furthermore, FOXO4-DRI could increase the percentage of type 2 alveolar epithelial cells (AEC2) and fibroblasts, and decrease the myofibroblasts in bleomycin (BLM)-induced PF mouse model.

Compared with mouse and human lung fibroblast cell lines, FOXO4‐DRI is inclined to kill TGF‐β‐induced myofibroblast in vitro. The inhibited effect of FOXO4‐DRI on myofibroblast lead to a downregulation of extracellular matrix (ECM) receptor interaction pathway in BLM‐induced PF. Above all, FOXO4‐DRI ameliorates BLM‐induced PF in mouse and may be served as a viable therapeutic option for PF.” (3)

"FOXO4‐D‐Retro‐Inverso(FOXO4‐DRI) ameliorates bleomycin (BLM)‐induced pulmonary fibrosis (PF).":

"FOXO4‐DRI improves the impaired ratio of lung cells.":

"FOXO4‐DRI works on the extracellular matrix (ECM) receptor interaction pathway to mitigate BLM‐induced PF... FOXO4‐DRI downregulates expression of proteins in ECM (extracellular matrix) receptor interaction.":

"FOXO4‐DRI alleviates myofibroblast differentiation in BLM‐induced PF mouse.":

Recently, investigators suggested using Mesenchymal stem cells (MSCs)–derived exosomes as a therapy for different conditions, including Parkinson's Disease (PD).^[1,2,5] MSCs can be found in various body parts and specialize in different cell types depending on the body's needs.^[1] These cells produce extracellular vesicles called exosomes that have been studied as an alternative medicinal agent because of their stability and biological prospect in terms of the substances they carry, like signaling molecules, cytokines, enzymes, and micro-RNA (miRNA).^[1,2,4] All these components are essential in maintaining cellular homeostasis, while the miRNA is more involved in regulating gene expression. ^[1,2,4] Many studies with MSCs have demonstrated several benefits in other neuropathological conditions. ^[1] One of the insights is that the MSCs have been pointed to activate different neuro-regeneration processes, opening a door for many possible ways to serve as promising therapies for future clinical trials. ^[1,3] Two targets for developing new treatments using MSCs are PD and Alzheimer's disease (AD). ^[2,3,4,7] PD is characterized by the deterioration of dopaminergic neurons and the insufficiency of dopamine production. ^[3,6,9] Generally, the decrease of dopaminergic neurons is related to the accumulation of Lewy bodies (protein aggregates of α-synuclein) inside the neurons, which affects the normal functioning of those cells.^[9] Interestingly, MSCs-derived exosome seems to be able to decrease one of the leading causes of PD, neuroinflammation.^[2,5,10] On the other hand, AD is described as a brain illness that presents as neurological hallmarks the formation of amyloid plaques (Aβ) and neurofibrillary tangles causing synaptic loss.^[4,7,12]

Retatrutide is a notable triple-agonist peptide, which means it targets three different hormone receptors: GLP-1 (glucagon-like peptide-1), GIP (gastric inhibitory polypeptide), and glucagon. These hormones play vital roles in regulating blood sugar, appetite, and energy expenditure, making Retatrutide a promising candidate for treating obesity and potentially type 2 diabetes mellitus.