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Subtle activation of a small subset of neurons in one region of the brain can make male mice resilient to, and even reverse, the detrimental effects of chronic stress. The same is true for female mice, but in a totally different region of the brain.

Researchers at Penn State reported these findings in two studies published in the journal Molecular Psychiatry and said the results could help explain the efficacy, or lack thereof, of certain antidepressant drugs and inform the development of new drugs and therapies.

The team developed a protocol to continuously activate neurons that produce the signaling molecule somatostatin, which helps regulate several biological processes, in specific brain regions in mice. The researchers found that doing so in a region of the brain called the prelimbic cortex made male mice resilient to stress, but failed to do so in female mice.

Researchers unveil how biological sex influences brain aging, revealing genetic, hormonal, and molecular mechanisms behind cognitive resilience and decline.

Gray matter is made up of neuron cell bodies and dendrites and is responsible for processing and interpreting information, such as sensation, perception, learning, speech, and cognition. White matter is made up of axons, which are long nerve fibers that connect neurons together from different parts of the brain.

In the study, male brains tended to be greater in volume than female brains. When adjusted for total brain volume, female infants on average had significantly more gray matter, while male infants on average had significantly more white matter in their brains.

Yumnah Khan, a Ph.D. student at the Autism Research Center at the University of Cambridge, who led the study, said, Our study settles an age-old question of whether male and female brains differ at birth. We know there are differences in the brains of older children and adults, but our findings show that they are already present in the earliest days of life.

Meanwhile, scientists dug into how psychedelics and MDMA fight off depression and post-traumatic stress disorders. The year was a relative setback for the psychedelic renaissance, with the FDA rejecting MDMA therapy. But the field is still gaining recognition for its therapeutic potential.

Then there’s lenacapavir, a shot that protects people from HIV. Named “breakthrough of the year” by Science, the shot completely protected African teenage girls and women against HIV infection. Another trial supported the results, showing the drug protected people who have sex with men at nearly 100 percent efficacy. The success stems from a new understanding of the protein “capsule” guarding the virus’ genetic material. Many other viruses have a similar makeup—meaning the strategy could help researchers design new drugs to fight them off too.

So, what’s poised to take the leap from breakthrough to clinical approval in 2025? Here’s what to expect in the year ahead.

DOI: Abstract We are living in a historical period in respect to the deterioration in public health, as we experience the rise of the catastrophic obesity epidemic and mental health crisis in recent decades, despite the great efforts from the scientific and medical community to seek health solutions and to try to find cures to the enormous human suffering and economic costs resulting by this collapse in public health. This trend has reached such a critical level that it jeopardizes society when over 40% of the population is obese in the United States, suffering grave medical health conditions, even as the expenditure on public health is rising exponentially to over 20% of gross domestic product. This should point to a monumental failure in our fundamental understanding of basic human biology and health. This article suggests that our current Western reductionist scientific paradigm in both biology and medicine has proved impotent and failed us completely. Therefore, the current cultural health crises require a more holistic approach to human biology and health in terms of chronobiological trends. The emerging neuroscience of brain energy metabolism will be considered as a holistic model for understanding how solar cycles affect our civilization and drive our sex and growth hormones and neurotransmitters that shape both our physical and mental health.

Aging happens in distinct stages marked by synchronized cellular changes across organs, as shown in Rockefeller’s largest-ever mammalian aging atlas. Their findings offer clues for targeting aging processes and reveal key age and sex differences in cellular dynamics.

If you compared photos of a maple tree taken in July and December, the difference would be striking: a vibrant green canopy in summer versus bare, stark branches in winter. What those images wouldn’t reveal is how the transformation unfolded—whether it was gradual or sudden. In reality, deciduous trees usually wait for environmental cues, such as changes in light or temperature, before shedding all their leaves within a brief span of one to two weeks.

When it comes to aging, we may be more like these trees than we realized.

By Sher Bahadur Poudel & Shoshana Yakar et al.

Several mouse lines with congenital growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis disruption have shown improved health and extended lifespan. The current study investigated how inactivating this axis, specifically during aging, impacts the healthspan. We used a tamoxifen-inducible global GH receptor (GHR) knockout mouse model starting at 12 months and followed the mice until 24 months of age (iGHRKO_12–24 mice). We found sex-and tissue-specific effects, with some being pro-aging and others anti-aging. Measuring an array of cytokines in serum revealed that inactivation of the GH/IGF-1 axis at 12 months did not affect systemic inflammation during aging. On the other hand, hypothalamic inflammation was significantly reduced in iGHRKO_12–24 mice, evidenced by GFAP⁺ (glial fibrillary acidic protein, a marker of astrocytes) and Iba-1⁺ (a marker for microglia). Liver RNAseq analysis indicated feminization of the male transcriptome, with significant changes in the expression of monooxygenase, sulfotransferase, and solute-carrier-transporter gene clusters. Finally, we found impaired bone morphology, more pronounced in male iGHRKO_12–24 mice and correlated with GH/IGF-1 inactivation onset age. We conclude that inhibiting the GH/IGF-1 axis during aging only partially preserves the beneficial healthspan effects observed with congenital GH deficiency.

Inactivating the GH axis during aging has sex-and tissue-specific effects on healthspan. Deleting the GH receptor (GHR) in the entire body at 12 months of age led to feminizing the male liver transcriptome, significantly altering the expression of p450 and sulfotransferase gene clusters. While GHR deletion during aging did not impact systemic inflammation, it was linked to reduced hypothalamic inflammation. Additionally, we observed impaired bone morphology, particularly in male mice, which correlated with the age at which GH/IGF-1 inactivation began. Our findings suggest that inhibiting the GH axis during aging only partially maintains the beneficial healthspan effects seen with congenital GH deficiency.

Continue reading “The impact of inactivation of the GH/IGF axis during aging on healthspan” »

Inhibiting TLR7, an immune signaling protein, may help preserve the protective layer surrounding nerve fibers in the brain during both Alzheimer’s disease and ordinary aging, suggests a study led by researchers at Weill Cornell Medicine. The research is published in the journal Science.

Most nerve fibers in vertebrates are encased in sheaths made largely of myelin, a protein that protects the fibers and greatly enhances the efficiency of their signal conduction. The destruction of myelin sheaths—demyelination—can occur in the context of brain inflammation and can lead to cognitive, movement and other neurological problems. The phenomenon is seen in multiple sclerosis (MS), Alzheimer’s, Parkinson’s and other neurological conditions, as well as in ordinary aging.

Demyelination-linked disorders often show sex differences, and in the study, the researchers looked for underlying mechanisms of demyelination that might help explain these differences. Their experiments in mouse models of Alzheimer’s uncovered TLR7 as a driver of inflammatory demyelination especially in males, but also showed that removing or inhibiting this immune protein can protect against demyelination in both males and females.

We further investigated whether these associations were driven by caffeine by performing two meta-analyses on the PREDICT1 and PREDICT3 22UKA samples for which the intake of decaffeinated and caffeinated coffee was available. Partial correlations between SGB-ranked abundances and decaffeinated versus caffeinated coffee were run independently (excluding individuals who drank exclusively caffeinated or decaffeinated coffee, respectively). In addition, partial correlations were also adjusted for the other type of coffee consumed by the individuals in case their record reported both kinds. We identified 150 correlations, which remained highly significant after controlling for the decaffeinated coffee intake (q 0.001, n_participants = 12,089; Extended Data Fig. 4c and Supplementary Table 8). This indicated a substantial independence on caffeine of the observed impact on the microbiome. Next, we analysed the decaffeinated coffee association with the microbiome in individuals consuming decaffeinated coffee and adjusting by caffeinated coffee as well as by sex, age and BMI. In this reduced set of samples (n_participants = 6,089) we identified 22 correlations at q 0.001 and 66 at q 0.1 (Supplementary Table 9). The top three correlations identified were L. asaccharolyticus (ρ = 0.27 (0.21–0.33), q 10⁻¹⁰), the Lachnospiraceae SGB4777 (ρ = 0.18 (0.16–0.21), q 10⁻¹⁰), and M. coli (SGB29305, ρ = 0.17 (0.13–0.2), q 10⁻¹⁰; Fig. 2b).

As expected, several coffee-associated SGBs were also L. asaccharolyticus co-abundant SGBs, possibly indicating similar independent stimulatory effects of coffee rather than ecological relations (Extended Data Fig. 5 and Supplementary Table 10). The top-five SGBs associated with L. asaccharolyticus abundance were, however, not among the strongest associations with coffee. In particular, the two SGBs with the strongest co-abundance pattern with L. asaccharolyticus were Dysosmobacter welbionis (SGB15078) and the Clostridiales bacterium SGB15143 (ρ = 0.57 and 0.51, respectively, q 1 × 10⁻¹⁰; Extended Data Fig. 5), which were both only weakly associated with total coffee (ρ ≤ 0.05; Supplementary Table 7). Overall, these results indicate that a panel of species, and in particular L. asaccharolyticus is robustly associated with total and decaffeinated coffee consumption, suggesting that the association is not purely due to caffeine.

Among the top coffee-associated SGBs, L. asaccharolyticus showed the highest and the most uniform prevalence across all the cohorts (93.5%; Fig. 2c). In the ‘never’ group from the USA, its prevalence was uniformly high (average prevalence of 87.8 ± 2%) across nine different regions (samples from PREDICT2 and PREDICT3 US22A, n = 9,210). Over and above this, however, it was uniformly increased in all regions when considering coffee consumption; it increased from 87.8% to 95.6% in moderate drinkers and from 95.6% to 97.7% in high drinkers (Fig. 2d and Supplementary Table 11). Degree of urbanization (rural versus urban living context) was not associated with L. asaccharolyticus in the microbiome (Extended Data Fig. 6 and Supplementary Table 12). Overall, the median abundance of L. asaccharolyticus ranged from 4.5-to 8-fold higher in the high compared with the never group (in the PREDICT3 US22A and MBS–MLVS cohorts), and 3.4-to 6.4-fold higher in the moderate versus the never group (in the PREDICT2 and MBS–MLVS cohorts; Supplementary Table 13). By contrast, the highest median fold change between moderate and high drinkers was only 1.4 and did not reach statistical significance in three out of five cohorts (Fig. 3a and Supplementary Table 14).