Outpace Aging

Why do levels of nicotinamide adenine dinucleotide (NAD+), a coenzyme found in all living cells that fuels mitochondrial energy production and DNA repair, drop by roughly half as mammals enter old age? Researchers at the Shenzhen Institute of Advanced Technology publishing in iScience asked whether an age-activated protein-cutting enzyme called asparagine endopeptidase (AEP) directly drives this energy collapse by destroying the enzyme that manufactures NAD+.

To test this, the team fed an oral, brain-permeable AEP blocker called compound #11a to naturally aging mice starting at 18 months of age, roughly equivalent to a 60-year-old human. They tracked survival, insulin sensitivity, and memory performance against untreated control mice for the remainder of their lives.

Blocking AEP produced remarkable whole-body rejuvenation. While untreated control mice lived an average of 24 months, mice given compound #11a starting at 18 months lived an average of 28 months, a 17 percent increase in total lifespan and a 67 percent increase in remaining life expectancy from the start of treatment. The researchers found that as animals age, rising AEP levels physically slice apart NAMPT, the master enzyme that recycles cellular building blocks back into fresh NAD+. Protecting NAMPT with compound #11a restored youthful NAD+ levels and boosted sirtuin 1 (SIRT1), a longevity protein that repairs DNA and stabilizes mitochondria. Treated mice showed lower multi-organ inflammation, improved insulin sensitivity, stronger motor coordination, and sharper memory in maze testing.

Senescent cells are damaged cells that permanently stop dividing but refuse to die, accumulating in aging organs and releasing inflammatory proteins that harm neighboring tissue. Scientists have tried building vaccines to train the immune system to clear these cells, but older immune systems respond poorly because their dendritic cells, the scout cells that teach T-cells what to attack, have become senescent themselves. A research team publishing in Advanced Science asked whether a single nanovaccine could rejuvenate aged dendritic cells while simultaneously training them to hunt down senescent fat cells.

The researchers engineered a dual-action nanovaccine wrapped in a specialized spider-silk protein scaffold and loaded with Gpnmb, a surface marker heavily concentrated on senescent fat cells. They tested the vaccine in naturally aged mice and mice fed a high-fat diet, comparing it against standard vaccine formulas lacking the spider-silk scaffold.

The spider-silk scaffold acted like a youth serum for the immune system itself. It quieted senescence stress signals inside aged dendritic cells, restoring their ability to present targets and unleashing killer CD8+ T-cells that selectively wiped out Gpnmb-positive senescent fat cells in visceral fat. Vaccinated mice cleared excess liver fat, restored healthy insulin sensitivity, and showed steep reductions in tissue senescence markers. In the survival cohort, median lifespan rose from 79 weeks in the control vaccine group to 91 weeks in the spider-silk nanovaccine group, a 12-week median survival gain.

Can cellular aging inside one small region of the brain accelerate physical aging and inflammation across the rest of the body? Researchers publishing in Aging Cell investigated fibroblast growth factor 13 (FGF13), an internal signaling protein that stays inside brain cells, to see why it drops sharply with age and whether restoring it in non-neuronal support cells could protect both memory and whole-body health.

The team first analyzed brain tissue from young and old mice and macaque monkeys, finding that FGF13 plunges with age inside astrocytes, the star-shaped glial support cells that nourish neurons, specifically within the prefrontal cortex (the brain's executive control center). They then deleted astrocytic FGF13 in young mice and, in a second experiment, used viral gene delivery to restore FGF13 in prefrontal cortex astrocytes of aged mice, testing spatial memory alongside blood and organ aging markers.

Deleting FGF13 in the brain's astrocytes of young mice triggered rapid memory loss and brain inflammation, and surprisingly drove whole-body aging: inflammatory blood markers interleukin-6 (IL-6) and interferon-gamma spiked, while senescence markers surged in the liver, kidneys, spleen, and skin. Conversely, restoring FGF13 in prefrontal astrocytes of old mice brought spatial memory back to near-young levels and significantly reduced inflammation and cellular senescence across peripheral organs. Mechanistically, FGF13 reactivated autophagy, the cell's internal recycling system that digests damaged proteins before they trigger inflammatory cascades.

Why do some older adults keep razor-sharp memory into their 80s and 90s despite carrying age-related brain changes, a trait neuroscientists call cognitive resilience? Researchers at Mass General Brigham, the Harvard Stem Cell Institute, and the Broad Institute publishing in Nature Neuroscience asked whether aging memory neurons actively release protective enzymes to keep neighboring brain circuits healthy.

Screening memory-forming neurons in the mouse hippocampus, the team identified a gene that produces PLA2G2F, a secreted phospholipase enzyme released outside the neuron to break down specific fats. They checked human brain tissue databases to confirm its link to human cognitive resilience, deleted the enzyme in mouse hippocampal neurons, boosted its production in aging mice from 12 to 16 months of age, and tested how it affects human microglia (the brain's resident immune cells) grown from reprogrammed adult stem cells.

In both aging mice and cognitively resilient older humans, neurons ramped up PLA2G2F production as a natural shield. Deleting the enzyme in mice caused severe synapse loss, clogged brain immune cells with toxic fat droplets, and accelerated memory decline. Conversely, boosting PLA2G2F in aging mice protected hippocampal connections and preserved youthful memory. When applied to human stem-cell-derived microglia in the lab, neuronal PLA2G2F acted as a broadcast signal that purged toxic lipid droplets and cholesterol esters from the immune cells, preventing them from turning inflammatory.

Testing whether a longevity therapy extends human life normally takes decades, creating a massive bottleneck for clinical trials. Epigenetic clocks, which are machine-learning algorithms that estimate biological age by reading chemical methyl tags on DNA, offer a way to measure age reversal in months, but scientists lacked proof of which clocks reliably respond to real human treatments. The Biomarkers of Aging Consortium, publishing in Nature Medicine, built the largest harmonized human interventional database ever assembled to find out.

The researchers created TranslAGE, a unified database combining 51 human longitudinal clinical trials covering structured exercise, caloric restriction, lifestyle programs, and longevity drugs. Across blood and tissue samples from all 51 studies, they calculated 16 leading epigenetic clocks and 94 additional DNA methylation biomarkers to see which algorithms consistently register biological age changes after proven interventions.

The benchmark revealed a sharp divide. First-generation clocks trained simply to guess a person's birth year responded poorly and inconsistently to treatments. In contrast, newer clocks trained to predict mortality risk and the speed of physiological decline, led by DunedinPACE (which measures how fast your body is aging per calendar year) and PCGrimAge, showed strong, consistent reductions across both lifestyle and drug trials. Anti-inflammatory drugs and structured metabolic lifestyle protocols produced the fastest drops in epigenetic aging pace, while early human senolytic trials showed more variable responses depending on trial length.