Interacting NAD and Cell Senescence Pathways Complicate Antiaging Therapies.

During human aging, decrease of NAD levels is associated with potentially reversible dysfunction in the liver, kidney, skeletal and cardiac muscle, endothelial cells, and neurons. At the same time, the number of senescent cells, associated with damage or stress that secretes proinflammatory factors (SASP or senescence-associated secretory phenotype), increases with age in many key tissues, including the kidneys, lungs, blood vessels, and brain. Senescent cells are believed to contribute to numerous age-associated pathologies and their elimination by senolytic regimens appears to help in numerous preclinical aging-associated disease models, including those for atherosclerosis, idiopathic pulmonary fibrosis, diabetes, and osteoarthritis.

Regulation of S-Nitrosylation in Aging and Senescence.

Nitric oxide signals through several distinct mechanisms, including interaction with the heme group of guanylyl cyclase enzymes resulting in modulation of cGMP levels in the vascular endothelium. Alternatively, reactive nitrogen oxide species can bind cysteine residues in target proteins forming S-nitrosothiols. S-nitrosylation is recognized as an important post-translational modification of dozens of proteins, which plays a key role in cellular homeostasis, metabolism, and various disease states.

Cellular Senescence as the Key Intermediate in Tau-Mediated Neurodegeneration.

Neuroinflammation is thought to play a key role in the progression of neurodegenerative disease such as Alzheimer's disease (AD). Given the apparent nexus of inflammatory disease with the secretory-associated senescence phenotype (SASP) of cellular senescence, two reports found that tau-mediated neurodegeneration involves induction of senescence in astrocytes, microglia, and possibly even neurons. Elimination of senescent cells by pharmacologically induced genetic ablation or by senolytic drugs blocks progression of mutant human tau-mediated neurodegeneration in mice.

Prevention of Senescence in Vasculature Through Quiescence.

Prevention of cell senescence is a potential means to extend healthspan and perhaps lifespan. Agents that increase NAD+ levels, which are diminished with age, may be senopreventive through restoration of SIRT1 and normal mitochondrial activity. The ketone body [Formula: see text]-hydroxybutyrate ([Formula: see text]-HB) prevents senescence by inducing quiescence in endothelial cells.

Mitochondrial-Derived Peptides Exacerbate Senescence.

Mitochondrial-derived peptides (MDPs), encoded by mitochondrial DNA, play a cytoprotective role by helping preserve mitochondrial function and cell viability under stressful conditions. Humanin and its homologs and MOTS-c are two of several MDPs hypothesized to have antiaging activity based on correlative studies. For example, humanin plasma levels are inversely correlated with growth hormone and insulin-like growth factor 1 expression, which may promote accelerated aging.

Finally, a Regimen to Extend Human Life Expectancy.

The United States has the most expensive healthcare system worldwide. Yet measures of health span and life expectancy are well below the major industrialized nations. With the U.

Telomerase May Paradoxically Accelerate Aging of the DNA Methylome.

DNA methylation (DNAm) clocks such as the Horvath DNAm clock provide the most accurate biological determination of biological age relative to chronological age available today. However, there is little correlation between DNAm clocks, telomere-based aging clocks, and transcriptomic-based aging clocks. Recently, a genome-wide association study identified single-nucleotide polymorphism variants of TERT, the gene that encodes telomerase, as accelerating intrinsic aging in the Horvath DNAm clock.

ATP Synthase, a Target for Dementia and Aging?

Advancing age is the biggest risk factor for development for the major life-threatening diseases in industrialized nations accounting for >90% of deaths. Alzheimer's dementia (AD) is among the most devastating. Currently approved therapies fail to slow progression of the disease, providing only modest improvements in memory.

Mesenchymal Stem Cells for Frailty?

Frailty is a medical syndrome associated with advancing age characterized by reduced functional reserve, strength, endurance, and susceptibility to infection associated with high morbidity, hospitalization, and death. Nonspecific interventions to improve the healthspan of affected patients include physical therapy, exercise, improved nutrition, etc. Among the hallmarks of aging, depletion of stem cells with resultant compromise of regeneration and repair of tissues informs a rational stem cell-based replacement strategy.

Pharmaceutical Rejuvenation of Age-Associated Decline in Spatial Memory.

Spatial memory and cognition decline during aging. Montelukast, an FDA approved drug for the treatment of asthma, can restore spatial memory in old rats to levels similar to those of young animals. Treatment improves three hallmarks of aging in the brain: reducing microglial-mediated neuroinflammation, blood-brain barrier (BBB) permeability, and increasing neurogenesis in the hippocampus although not completely to youthful levels.

Reversal of Aged Muscle Stem Cell Dysfunction.

The loss of muscle stem cell (MuSC) numbers and function in the elderly results in a dramatic delay or incomplete repair of muscle following injury or surgery. Prolonged immobility can exacerbate the loss of muscle mass with increased morbidity of affected patients. Stem cells and their niche cooperate to regulate the activation, self-renewal, differentiation, and return to quiescence of MuSCs.

Uncoupling Mitochondrial Respiration for Diabesity.

Until recently, the mechanism of adaptive thermogenesis was ascribed to the expression of uncoupling protein 1 (UCP1) in brown and beige adipocytes. UCP1 is known to catalyze a proton leak of the inner mitochondrial membrane, resulting in uncoupled oxidative metabolism with no production of adenosine triphosphate and increased energy expenditure. Thus increasing brown and beige adipose tissue with augmented UCP1 expression is a viable target for obesity-related disorders.

Preclinical Reversal of Atherosclerosis by FDA-Approved Compound that Transforms Cholesterol into an Anti-Inflammatory "Prodrug".

Although atherosclerosis is treatable with lipid-lowering drugs, not all patients respond. Hydroxypropyl-beta-cyclodextrin (CD) is an FDA-approved compound for solubilizing, capturing, and delivering lipophilic drugs in humans. Zimmer et al.

Rejuvenating Muscle Stem Cell Function: Restoring Quiescence and Overcoming Senescence.

Elderly humans gradually lose strength and the capacity to repair skeletal muscle. Skeletal muscle repair requires functional skeletal muscle satellite (or stem) cells (SMSCs) and progenitor cells. Diminished stem cell numbers and increased dysfunction correlate with the observed gradual loss of strength during aging.