Response to Hypoxia in Cognitive Decline.

Inflammaging, the increase of proinflammatory processes with increasing age, has multiple mechanisms from increasing numbers of senescent cells secreting cytokines to changes in metabolic processes. Alterations of oxygen metabolism with aging, especially decreased levels of O with age resulting from endocrine and cardiovascular dysfunction as well as desensitization of cellular response to hypoxia, may exacerbate inflammaging, which in turn creates further oxygen metabolic dysfunction. During aging, decline in levels of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), BPG mutase, and adenosine A2B receptor, a key adenosine signaling receptor that can augment 2,3-BPG expression, may fail to protect sensitive brain tissue from subtly reduced O levels, in turn resulting in increased numbers of activated microglia and secretion of proinflammatory cytokines, ultimately promoting inflammaging and senescence of endothelial cells.

The NAD+/PARP1/SIRT1 Axis in Aging.

NAD+ levels decline with age in diverse animals from Caenorhabditis elegans to mice. Raising NAD+ levels by dietary supplementation with NAD+ precursors, nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), improves mitochondrial function and muscle and neural and melanocyte stem cell function in mice, as well as increases murine life span. Decreased NAD+ levels with age reduce SIRT1 function and reduce the mitochondrial unfolded protein response, which can be overcome by NR supplementation.

Thymus Maintenance and Regeneration by Specific Molecular Factors.

Although the thymus plays a key role in T cell maturation in mammals, it begins to atrophy and involute at sexual maturity. The diminished thymic microenvironment is thought to contribute to reduced adaptive immune function during aging, leading to the increased likelihood of infectious diseases and cancer. Caloric restriction or ectopic expression of the pro-longevity growth factor fibroblast growth factor 21 has been reported to maintain the thymus in aging mice.

Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence.

Reduced telomere length with increasing age in dividing cells has been implicated in contributing to the pathologies of human aging, which include cardiovascular and metabolic disorders, through induction of cellular senescence. Telomere shortening results from the absence of telomerase, an enzyme required to maintain telomere length. Telomerase reverse transcriptase (TERT), the protein subunit of telomerase, is expressed only transiently in a subset of adult somatic cells, which include stem cells and smooth muscle cells.

Stem Cell Depletion by Global Disorganization of the H3K9me3 Epigenetic Marker in Aging.

Epigenomic change and stem cell exhaustion are two of the hallmarks of aging. Accumulation of molecular damage is thought to underlie aging, but the precise molecular composition of the damage remains controversial. That some aging phenotypes, especially those that result from impaired stem cell function, are reversible suggest that such "damage" is repairable.

Telomerase redux: ready for prime time?

By maintaining genome integrity, controlling cell proliferation, and regulating tissue homeostasis, telomerase plays a critical role in the pathology of aging and cancer. Telomerase is composed of telomerase RNA, or telomerase RNA component (TERC), which serves as a template for telomeric DNA synthesis, and a catalytic subunit, telomerase reverse transcriptase (TERT). The canonical function of TERT is the synthesis of telomeric DNA repeats and the maintenance of telomere length.

Systemic factors mediate reversible age-associated brain dysfunction.

Brain function declines in aging mammals. Recent work has identified dysregulation of key blood-borne factors whose altered expression during aging diminishes brain function in mice. Increased C-C motif chemokine 11 (CCL11) expression with aging is detrimental to brain function.

Prolonged fasting/refeeding promotes hematopoietic stem cell regeneration and rejuvenation.

The sensitivity of hematopoietic stem cells (HSCs) to toxic effects of cancer chemotherapy is one of the major roadblocks in cancer therapy. Moreover, the loss of HSC function in the elderly ("immunosenescence") is a major source of morbidity and mortality. Until recently, it was believed that HSCs were irreversibly damaged by the aging process.

Paradoxical effects of antioxidants on cancer.

Antioxidants have had a checkered history concerning their reported ability to prevent or treat cancer. Early studies that showed ascorbate had benefit in cancer were followed by more definitive studies that demonstrated no benefit. Recent work suggests that biological context may be key to predicting whether antioxidants impede or even promote tumorigenesis.

Partial reversal of skeletal muscle aging by restoration of normal NAD⁺ levels.

That some aging-associated phenotypes may be reversible is an emerging theme in contemporary aging research. Gomes et al. report that age-associated oxidative phosphorylation (OXPHOS) defects in murine skeletal muscle are biphasic.

Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases.

Decline of cognition and increasing risk of neurodegenerative diseases are major problems associated with aging in humans. Of particular importance is how the brain removes potentially toxic biomolecules that accumulate with normal neuronal function. Recently, a biomolecule clearance system using convective flow between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) to remove toxic metabolites in the brain was described.

Trade-offs between anti-aging dietary supplementation and exercise.

In otherwise healthy adults, moderate aerobic exercise extends life span and likely health span by 2-6 years. Exercise improves blood sugar regulation, and resistance exercise increases or maintains muscle mass and is associated with improved cognitive function. On the other hand, evidence for anti-oxidant supplements increasing longevity in humans is lacking.

Rejuvenation of aging hearts.

Specific subtle changes in regulation or activity of factors that maintain homeostasis and cell differentiation may play significant roles in mammalian aging. Drift resulting from reaching the end of an organism's developmental program might involve a specific ordered set of changes. Several studies have suggested that dysfunctional changes associated with aging in skeletal muscle, neurons, and hematopoietic stem cells may be caused by specific changes either in the extracellular environment or in intracellular regulatory networks and that such dysfunction may be reversible.

Dietary modification of the microbiome affects risk for cardiovascular disease.

The incidence of cardiovascular disease (CVD) increases with age and is associated with some syndromes that exhibit aspects of premature aging, such as progeria. Various factors are thought to contribute to the progression of CVD, including hypertension, hypercholesterolemia, diets rich in saturated and trans fats, etc. Recent reports have uncovered an important connection between diet, the microbiome, and CVD.

Rejuvenation of adult stem cells: is age-associated dysfunction epigenetic?

The dysfunctional changes of aging are generally believed to be irreversible due to the accumulation of molecular and cellular damage within an organism's somatic cells and tissues. However, the importance of potentially reversible cell signaling and epigenetic changes in causing dysfunction has not been thoroughly investigated. Striking evidence that increased oxidative stress associated with hematopoietic stem cells (HSCs) from aging mice causes dysfunction has been reported.

The DNA methylome as a biomarker for epigenetic instability and human aging.

Methylation of DNA is intimately involved in control of mammalian/vertebrate gene expression as part of a complex epigenetic regulatory system. We hypothesize that DNA methylation at cytosine-phosphate-guanine sites (CpGs), the "DNA methylome," evolved to increase stability of the differentiated state in somatic vertebrate cells, especially post-mitotic cells, which may have helped to increase longevity. Therefore, the DNA methylome may play a key role in human aging and be an ideal source of biomarkers aging.

Dietary restriction: critical co-factors to separate health span from life span benefits.

Dietary restriction (DR), typically a 20%-40% reduction in ad libitum or "normal" nutritional energy intake, has been reported to extend life span in diverse organisms, including yeast, nematodes, spiders, fruit flies, mice, rats, and rhesus monkeys. The magnitude of the life span enhancement appears to diminish with increasing organismal complexity. However, the extent of life span extension has been notoriously inconsistent, especially in mammals.

Dissecting mammalian target of rapamycin to promote longevity.

Treatment with rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1) can increase mammalian life span. However, extended treatment with rapamycin results in increased hepatic gluconeogenesis concomitant with glucose and insulin insensitivity through inhibition of mTOR complex 2 (C2). Genetic studies show that increased life span associated with mTORC1 inhibition can be at least partially decoupled from increased gluconeogenesis associated with mTORC2 inhibition.

Epigenetic-mediated decline in synaptic plasticity during aging.

Cognitive decline observed in aging mammals is associated with decreased long-term synaptic plasticity, especially long-term potentiation (LTP). Recent work has uncovered a connection between LTP, histone acetylation, and brain-derived neurotrophic factor (BDNF)/neurotrophin receptor B (trkB) signaling. LTP, histone acetylation, and BDNF/trkB signaling decrease in old animals, Because an apparent positive feedback loop links these processes, treatment with histone deacetylase inhibitors or a trkB agonist restores LTP in the hippocampus of old animals.

Reversing age-related decline in working memory.

Higher cognitive functions, such as working memory and the ability to focus attention, decline as people age. Recently, it has been reported that decline in working memory in aging rhesus monkeys correlates with the loss of activity of a specific set of neurons in the prefrontal cortex during a delay following a learning cue. The activity of these neurons can be rescued by stimulating α-2 adrenergic receptors, inhibiting cyclic adenosine monophosphate (cAMP) signaling, or closing potassium channels that are known to inhibit firing and synaptic connectivity.

Rapamycin as an antiaging therapeutic?: targeting mammalian target of rapamycin to treat Hutchinson-Gilford progeria and neurodegenerative diseases.

Mammalian target of rapamycin (mTOR), a serine/threonine kinase and component of the mTORC1 signaling complex, acts as an energy, nutrient, growth factor, stress, and redox sensor to increase protein synthesis and decrease macroautophagy. mTORC1 plays a central role in the maintenance of homeostasis and its deterioration, seen in aging. The Food and Drug Administration (FDA)-approved immunosuppressive macrolide rapamycin binds immunophilin FKBP12 (FK506-binding protein) to inhibit mTORC1.

Applied Healthspan engineering.

According to the Homeric Hymn to Aphrodite, when Eos asked Zeus for Tithonus to be granted immortality, she forgot to ask for eternal youth. Applied Healthspan Engineering (AHE) seeks to address this problem. All organisms have a minimal level of functional reserve required to sustain life that eventually declines to a point incompatible with survival at death.