The epigenome, which controls cell identity and function, is not maintained with 100% fidelity in somatic animal cells. Errors in the maintenance of the epigenome lead to epigenetic drift, an important hallmark of aging. Numerous studies have described DNA methylation clocks that correlate epigenetic drift with increasing age. The question of how significant a role epigenetic drift plays in creating the phenotypes associated with aging remains open. A recent study describes a new DNA methylation clock that can be slowed by caloric restriction (CR) in a way that correlates with the degree of lifespan and healthspan extension conferred by CR, suggesting that epigenetic drift itself is a determinant of mammalian lifespan. Genetic transplantation using genomic editing of DNA methylation homeostatic genes from long-lived to short-lived species is one way to potentially demonstrate a causative role for DNA methylation. Whether the DNA methylation clock be reset to youthful state, eliminating the effects of epigenetic drift without requiring a pluripotent cell intermediate is a critical question with profound implications for the development of aging therapeutics. Methods that transiently erase the DNA methylation pattern of somatic cells may be developed that reset this aging hallmark with potentially profound effects on lifespan, if DNA methylation-based epigenetic drift really plays a primary role in aging.

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. Unlike most other interventions tested to date, inhibition of mTORC1 by rapamycin extends life span in old mice, likely by a combination of increased autophagy and decreased mRNA translation. Hutchinson–Gilford progeria syndrome (HGPS) is a lethal genetic disorder affecting children that is characterized by symptoms of premature aging, such as atherosclerosis. Increased autophagy induced by rapamycin reduces accumulation of progerin, an alternate spliced form of lamin A/C, that forms insoluble toxic aggregates, resulting in reduced HGPS-associated nuclear blebbing, growth inhibition, epigenetic dysregulation, and genomic instability. Rapamycin-induced autophagy also suppresses symptoms in mouse models of Alzheimer, Parkinson, and Huntington diseases, where toxic insoluble protein aggregates accumulate. On the basis of these results, modulation of mTORC1 function is a promising target for the development of therapeutics for neurodegenerative diseases and HGPS. Rapamycin is the obvious candidate for near-term evaluation in the treatment of these diseases. However, the substantial set of rapamycin-associated adverse effects, as well as the lack of aging-specific human data, should caution the routine use of rapamycin as an antiaging agent. The use of safer, but perhaps weaker, indirect mTORC1 inhibitors, such as metformin and resveratrol, may prove useful. Further study will ascertain whether such compounds extend human health or life span.

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. These results coupled with exciting work on histone methylation and life span in Caneorhabditis elegans suggest that epigenetic changes may play a significant role in aging. Such dysfunctional epigenetic pathways may provide novel targets for cognitive enhancing therapeutics.

Presenting a panel of human hybridomas secreting serospecific antibodies which confer a high degree of protection against fatal infection with Pseudomonas aeruginosa, we report an efficient approach for a systematic generation of antigen specific hum

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. A new model that links the methylome to chronological age has been reported by Hannum et al. ¹ that accurately predicts age and rate of aging from the DNA methylation state of 71 markers in human blood samples. This model may make possible the development of new anti-aging therapeutics as well as more accurately assess the impact of anti-aging regimens, such as caloric restriction and drugs such as rapamycin. Furthermore, the model reveals information loss with increased age consistent with noise/unstable diffentiation-based models of aging. The model may eventually lead to experiments to differentiate the contributions of biomolecular damage and noise/incomplete structural replication during aging.

Intermittent fasting (IF) is the practice of restricting food intake for 12–48 hours per fasting cycle over a prolonged period of time. Previous study shows beneficial health effects such as weight loss and lower risk for cardiometabolic diseases. Although reduced calorie intake may account for some of the observed benefits of IF, exact mechanisms are still unclear. Recent evidence indicates that IF may lead to remodeling and increased taxonomic diversity in the human gut microbiome. In particular, the Lachnospiraceae family of anaerobic bacteria increased during fasting. This family, in the order Clostridiales, promotes butryogenesis in the gut, a process that is associated with healthful metabolic and prolongevity effects. IF-associated alterations to the microbiome may play a key role in the metabolic and potential healthspan-enhancing benefits of IF and dietary restriction.