Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP). Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence.

Past and Future Directions for Research on Cellular Senescence.

Cellular senescence was initially described in the early 1960s by Hayflick and Moorehead. They noted sustained cell-cycle arrest after repeated subculturing of human primary cells. Over half a century later, cellular senescence has become recognized as one of the fundamental pillars of aging.

Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans.

Background: α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential.

Strategies for late phase preclinical and early clinical trials of senolytics.

Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention.

SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3.

Senescent cells, which arise due to damage-associated signals, are apoptosis-resistant and can express a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). We recently reported that a component of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface protein, S1, can amplify the SASP of senescent cultured human cells and that a related mouse β-coronavirus, mouse hepatitis virus (MHV), increases SASP factors and senescent cell burden in infected mice. Here, we show that SARS-CoV-2 induces senescence in human non-senescent cells and exacerbates the SASP in human senescent cells through Toll-like receptor-3 (TLR-3).

Senolytics reduce coronavirus-related mortality in old mice.

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism.

Targeting CD38-dependent NAD metabolism to mitigate multiple organ fibrosis.

The processes underlying synchronous multiple organ fibrosis in systemic sclerosis (SSc) remain poorly understood. Age-related pathologies are associated with organismal decline in nicotinamide adenine dinucleotide (NAD) that is due to dysregulation of NAD homeostasis and involves the NADase CD38. We now show that CD38 is upregulated in patients with diffuse cutaneous SSc, and CD38 levels in the skin associate with molecular fibrosis signatures, as well as clinical fibrosis scores, while expression of key NAD-synthesizing enzymes is unaltered.

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD and NMN levels.

Decreased NAD levels have been shown to contribute to metabolic dysfunction during aging. NAD decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD homeostasis.

Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During Aging.

Background & Aims: Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear.

Clotrimazole is effective for the regression of endometriotic implants in a Wistar rat experimental model of endometriosis.

The present work aimed to evaluate molecular, angiogenic and inflammatory changes induced by clotrimazole (CTZ) on endometriosis lesions. For this, thirty female Wistar rats with surgically implanted autologous endometrium were treated with CTZ or vehicle (200 mg/kg) via esophageal gavage for 15 consecutive days. CTZ treatment significantly decreased the growth and the size of the implants, and histological examination indicated regression and atrophy, with no toxicity to the animals.

The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging.

Recent reports indicate that intracellular NAD levels decline in tissues during chronological aging, and that therapies aimed at increasing cellular NAD levels could have beneficial effects in many age-related diseases. The protein CD38 (cluster of differentiation 38) is a multifunctional enzyme that degrades NAD and modulates cellular NAD homeostasis. At the physiological level, CD38 has been implicated in the regulation of metabolism and in the pathogenesis of multiple conditions including aging, obesity, diabetes, heart disease, asthma, and inflammation.

Preclinical efficacy of the novel competitive NAMPT inhibitor STF-118804 in pancreatic cancer.

NAD salvage is one of the pathways used to generate NAD in mammals. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway, uses nicotinamide (NAM) to generate nicotinamide mononucleotide (NMN). NMN is one of the main precursors of NAD synthesis in cells.

The Use of NMR Metabolite Profiling and in vivo Hypoglycemic Assay for Comparison of Unfractionated Aqueous Leaf Extracts of Two Ocimum Species.

Ocimum basilicum and Ocimum gratissimum (Lamiaceae) are used to treat diabetes mellitus in Africa. In a previous work, we identified chicoric acid as a hypoglycemic substance in O. gratissimum.

Antidiabetic activity of Sedum dendroideum: metabolic enzymes as putative targets for the bioactive flavonoid kaempferitrin.

The aim of this study was to evaluate the antidiabetic potential of a leaf extract and flavonoids from Sedum dendroideum (SD). Additionally, our goals were to establish a possible structure/activity relationship between these flavonoids and to assess the most active flavonoid on the glycolytic enzyme 6-phosphofructo-1-kinase (PFK). SD juice (LJ), a flavonoid-rich fraction (BF), and separately five flavonoids were evaluated intraperitoneally for their acute hypoglycemic activity in normal and streptozotocin-induced diabetic mice.