Longevity Papers

Biological aging clocks across organs and omics data, including clinical phenotypes, neuroimaging, proteomics, and epigenetics, have proven instrumental in advancing our understanding of human aging and disease. Here, we expand this aging clock framework to plasma metabolomics by developing 5 organ-specific metabolome-based biological age gaps (MetBAGs) using 107 plasma non-derived metabolites from 274,247 UK Biobank participants. Our multi-organ MetBAGs were trained using Lasso regression and neural networks, achieving a mean absolute error of approximately 6 years (0.25

Aging is accompanied by considerable changes in the gut microbiome, yet the molecular mechanisms driving aging and the role of the microbiome remain unclear. Here we combined metagenomics, transcriptomics and metabolomics from aging mice with metabolic modelling to characterize host-microbiome interactions during aging. Reconstructing integrated metabolic models of host and 181 mouse gut microorganisms, we show a complex dependency of host metabolism on known and previously undescribed microbial interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome accompanied by reduced beneficial interactions between bacterial species. These changes coincided with increased systemic inflammation and the downregulation of essential host pathways, particularly in nucleotide metabolism, predicted to rely on the microbiota and critical for preserving intestinal barrier function, cellular replication and homeostasis. Our results elucidate microbiome-host interactions that potentially influence host aging processes. These pathways could serve as future targets for the development of microbiome-based anti-aging therapies.

Bisphosphonates (BPs) have been the major class of medicines used to treat disorders of excessive bone loss for over five decades. Recently it has been recognized that BPs may also have additional significant beneficial extra-skeletal effects. These include a reduction of all-cause mortality and of conditions commonly linked to ageing, such as cancer and cardiovascular disease. Here we show that bisphosphonates co-localize with lysosomal and endosomal organelles in non-skeletal cells and stimulate cell growth at low doses. In vivo spatial transcriptomic analysis revealed differentially expressed senescence markers in multiple organs of aged BP-treated mice, and a shift in cellular composition toward those of young counterparts. Similarly, a 5000-plex plasma proteome analysis from osteopenic patients before and after BP-treatment showed significant alterations in ~400 proteins including GTPase regulators and markers of senescence, autophagy, apoptosis, and inflammatory responses. Furthermore, treatment with BPs protected against the onset of senescence in vitro. Proteome-wide target deconvolution using 2D thermal profiling revealed novel BP-binding targets (PHB2, ASAH1), and combined with RNA- and ATAC-seq of BP-treated cells and patient data, suggests downstream regulation of the MEF2A transcription factor within the heart. Collectively, these results indicate how BPs may beneficially modify the human plasma proteome, and directly impact multiple non-skeletal cell types through previously unidentified proteins, thereby influencing a range of pathways related to senescence and ageing.

In light of increasing attention being paid to aging research globally, the accumulation of aging hallmarks and their corresponding targeting therapeutics have been substantially revealed. However, uncovering the genuine drivers within epigenetic alterations that lead to aging remains a formidable challenge. In this study, we identified tRNASec(NCA) as the most severely damaged tRNA species in the kidneys of naturally aged mice. This damage not only dysregulated selenoproteins with anti-aging effects, but also generates a 5\'-tRNA fragment cleaved at the 34th position, which accumulates in an age-dependent manner. Mechanistically, the 5\'-tRNASec(NCA) half interacts and activates Toll-like receptor 7, thereby triggering innate immune responses and promoting cellular senescence in both mice and human cells. Moreover, in a naturally aged mice model, administration of an antisense oligonucleotide (ASO) targeting the 5\'-tRNASec(NCA) half remarkably ameliorates aging markers, enhances telomere length, and extends healthspan and lifespan. In addition, ASO-5\'-tRNASec(NCA) half plays another role in directly targeting and downregulating BCAT1 via the RNAi pathway to intervene in the senescence process. Our findings underscore tRNA damage as a novel aging hallmark, and targeting the damage-induced products presents a novel strategy for aging intervention, thus expanding our knowledge of the aging process.

Aging is reflected by genome-wide DNA methylation changes, which form the basis of epigenetic clocks, but it is largely unclear how these epigenetic modifications are regulated and whether they directly affect the aging process. In this study, we performed epigenetic editing at age-associated CpG sites to explore the consequences of interfering with epigenetic clocks. CRISPR-guided editing targeted at individual age-related CpGs evoked genome-wide bystander effects, which were highly reproducible and enriched at other age-associated regions. 4C-sequencing at age-associated sites revealed increased interactions with bystander modifications and other age-related CpGs. Subsequently, we multiplexed epigenetic editing in human T cells and mesenchymal stromal cells at five genomic regions that become either hypermethylated or hypomethylated upon aging. While targeted methylation seemed more stable at age-hypermethylated sites, both approaches induced bystander modifications at CpGs with the highest correlations with chronological age. Notably, these effects were simultaneously observed at CpGs that gain and lose methylation with age. Our results demonstrate that epigenetic editing can extensively modulate the epigenetic aging network and interfere with epigenetic clocks.

Long-lived mammals are reported to have rare or considerably fewer instances of spontaneous tumors, suggesting they might have evolved specific or convergent mechanisms of cancer resistance to extend lifespan; however, the underlying mechanisms remain insufficiently explored. Here, we conducted comparative analysis across 60 mammalian genomes to investigate the genomic features associated with natural cancer resistance. We identified 296 strongly selected genes unique to long-lived species and associated with immune response, DNA repair, and cancer, which might contribute to cancer resistance and lifespan extension in long-lived species. Further, 229 convergent cancer-related genes were detected in the four extremely long-lived species and in-vitro assays confirmed a convergent mutation of LZTS1, shared by bowhead whales and naked mole rats, could suppress cancer development. Importantly, 16 genes were significantly related to both body weight and cancer, defined as candidate genes of Peto's paradox. Of them, the YAP1 gene, harboring the A214S mutation, was identified as a key gene that upregulated tumor suppression genes by localizing to the cytoplasm, which might prohibit cancer development in the large and long-lived cetaceans. These findings provide novel insights into the molecular mechanisms underlying natural cancer resistance in long-lived mammals and the biological basis of Peto's paradox.