Paleoproteomics sheds light on million-year-old fossils
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Reducing functionally defective old HSCs alleviates aging-related phenotypes in old recipient mice
Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process. Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit “younger” molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150low HSCs from old mice but not their CD150high counterparts can effectively differentiate into downstream lineage cells. Notably, transplantation of old CD150low HSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150high HSCs. Importantly, reducing the dysfunctional CD150high HSCs can alleviate aging phenotypes in old recipient mice. Thus, our study demonstrates the presence of “younger” HSCs in old mice, and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.
Exosome-based targeted delivery of NF-κB ameliorates age-related neuroinflammation in the aged mouse brain
Neuroinflammation, a significant contributor to various neurodegenerative diseases, is strongly associated with the aging process; however, to date, no efficacious treatments for neuroinflammation have been developed. In aged mouse brains, the number of infiltrating immune cells increases, and the key transcription factor associated with increased chemokine levels is nuclear factor kappa B (NF-κB). Exosomes are potent therapeutics or drug delivery vehicles for various materials, including proteins and regulatory genes, to target cells. In the present study, we evaluated the therapeutic efficacy of exosomes loaded with a nondegradable form of IκB (Exo-srIκB), which inhibits the nuclear translocation of NF-κB to suppress age-related neuroinflammation. Single-cell RNA sequencing revealed that these anti-inflammatory exosomes targeted macrophages and microglia, reducing the expression of inflammation-related genes. Treatment with Exo-srIκB also suppressed the interactions between macrophages/microglia and T and B cells in the aged brain. We demonstrated that Exo-srIκB successfully alleviates neuroinflammation by primarily targeting activated macrophages and partially modulating the functions of age-related interferon-responsive microglia in the brain. Thus, our findings highlight Exo-srIκB as a potential therapeutic agent for treating age-related neuroinflammation.
Bone loss with aging is independent of gut microbiome in mice
Emerging evidence suggests a significant role of gut microbiome in bone health. Aging is well recognized as a crucial factor influencing the gut microbiome. In this study, we investigated whether age-dependent microbial change contributes to age-related bone loss in CB6F1 mice. The bone phenotype of 24-month-old germ-free (GF) mice was indistinguishable compared to their littermates colonized by fecal transplant at 1-month-old. Moreover, bone loss from 3 to 24-month-old was comparable between GF and specific pathogen-free (SPF) mice. Thus, GF mice were not protected from age-related bone loss. 16S rRNA gene sequencing of fecal samples from 3-month and 24-month-old SPF males indicated an age-dependent microbial shift with an alteration in energy and nutrient metabolism potential. An integrative analysis of 16S predicted metagenome function and LC-MS fecal metabolome revealed an enrichment of protein and amino acid biosynthesis pathways in aged mice. Microbial S-adenosyl methionine metabolism was increased in the aged mice, which has previously been associated with the host aging process. Collectively, aging caused microbial taxonomic and functional alteration in mice. To demonstrate the functional importance of young and old microbiome to bone, we colonized GF mice with fecal microbiome from 3-month or 24-month-old SPF donor mice for 1 and 8 months. The effect of microbial colonization on bone phenotypes was independent of the microbiome donors’ age. In conclusion, our study indicates age-related bone loss occurs independent of gut microbiome.
Evidence from Tinshemet Cave in Israel suggests behavioural uniformity across Homo groups in the Levantine mid-Middle Palaeolithic circa 130,000–80,000 years ago
The south Levantine mid-Middle Palaeolithic (mid-MP; ~130–80 thousand years ago (ka)) is remarkable for its exceptional evidence of human morphological variability, with contemporaneous fossils of Homo sapiens and Neanderthal-like hominins. Yet, it remains unclear whether these hominins adhered to discrete behavioural sets or whether regional-scale intergroup interactions could have homogenized mid-MP behaviour. Here we report on our discoveries at Tinshemet Cave, Israel. The site yielded articulated Homo remains in association with rich assemblages of ochre, fauna and stone tools dated to ~100 ka. Viewed from the perspective of other key regional sites of this period, our findings indicate consolidation of a uniform behavioural set in the Levantine mid-MP, consisting of similar lithic technology, an increased reliance on large-game hunting and a range of socially elaborated behaviours, comprising intentional human burial and the use of ochre in burial contexts. We suggest that the development of this behavioural uniformity is due to intensified inter-population interactions and admixture between Homo groups ~130–80 ka.
A year above 1.5 °C signals that Earth is most probably within the 20-year period that will reach the Paris Agreement limit
The temperature goals of the Paris Agreement are measured as 20-year averages exceeding a pre-industrial baseline. The calendar year of 2024 was announced as the first above 1.5 °C relative to pre-industrial levels, but the implications for the corresponding temperature goal are unclear. Here we show that, without very stringent climate mitigation, the first year above 1.5 °C occurs within the first 20-year period with an average warming of 1.5 °C.
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