Longevity Papers

A Novel Metabolomic Aging Clock Predicting Health Outcomes and Its Genetic and Modifiable Factors.

Xueqing Jia, Jiayao Fan, Xucheng Wu ... · Metabolomics · Center for Clinical Big Data and Analytics of the Second Affiliated Hospital and Department of Big Data in Health Science School of Public Health, Zhejiang Key Laboratory of Intelligent Preventive Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. · pubmed

Existing metabolomic clocks exhibit deficiencies in capturing the heterogeneous aging rates among individuals with the same chronological age. Yet, the modifiable and non-modifiable factors in metabolomic aging have not been systematically studied. Here, a new aging measure-Metab...

Existing metabolomic clocks exhibit deficiencies in capturing the heterogeneous aging rates among individuals with the same chronological age. Yet, the modifiable and non-modifiable factors in metabolomic aging have not been systematically studied. Here, a new aging measure-MetaboAgeMort-is developed using metabolomic profiles from 239,291 UK Biobank participants for 10-year all-cause mortality prediction. The MetaboAgeMort showed significant associations with all-cause mortality, cause-specific mortality, and diverse incident diseases. Adding MetaboAgeMort to a conventional risk factors model improved the predictive ability of 10-year mortality. A total of 99 modifiable factors across seven categories are identified for MetaboAgeMort. Among these, 16 factors representing pulmonary function, body composition, socioeconomic status, dietary quality, smoking status, alcohol intake, and disease status showed quantitatively stronger associations. The genetic analyses revealed 99 genomic risk loci and 271 genes associated with MetaboAgeMort. The tissue-enrichment analysis showed significant enrichment in liver. While the external validation of the MetaboAgeMort is required, this study illuminates heterogeneous metabolomic aging across the same age, providing avenues for identifying high-risk individuals, developing anti-aging therapies, and personalizing interventions, thus promoting healthy aging and longevity.

Longevity Relevance Analysis (5)

The paper presents a novel metabolomic aging clock, MetaboAgeMort, which aims to predict health outcomes and identify modifiable factors associated with aging. This research is relevant to longevity as it addresses the heterogeneous nature of aging and seeks to understand the underlying biological mechanisms that contribute to health outcomes in aging individuals. The identification of modifiable factors and genetic associations provides valuable insights that could inform interventions aimed at promoting healthy aging. However, while the findings are significant, they primarily enhance existing knowledge rather than presenting a groundbreaking shift in the field, thus warranting a moderate impact score.

Tauroursodeoxycholic acid targets HSP90 to promote protein homeostasis and extends healthy lifespan.

Jia-Yu Liu, Yao Wang, Yue Guo ... · Taurochenodeoxycholic Acid · Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100850, China. · pubmed

As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health...

As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health benefits beyond liver protection. Here, we show that TUDCA extends the lifespan and healthspan of C. elegans. Importantly, oral supplementation of TUDCA improves fitness in old mice, including clinically relevant phenotypes, exercise capacity and cognitive function. Consistently, TUDCA treatment drives broad transcriptional changes correlated with anti-aging characteristics. Mechanistically, we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding activity. This collaboration further alleviates aging-induced endoplasmic reticulum (ER) stress and facilitates protein homeostasis, thus offering resistance to aging. In summary, our findings uncover new molecular links between an endogenous metabolite and protein homeostasis, and propose a novel anti-aging strategy that could improve both lifespan and healthspan.

Longevity Relevance Analysis (5)

Tauroursodeoxycholic acid (TUDCA) promotes protein homeostasis and extends lifespan and healthspan in C. elegans and mice. The paper addresses mechanisms related to aging and proposes a potential therapeutic strategy for improving lifespan and healthspan, which aligns with the goals of longevity research.

Delta Opioid Peptide [d-Ala2, d-Leu5]-Enkephalin Improves Physical and Cognitive Function and Increases Lifespan in Aged Female Mice.

Lixia Huo, Hongquan Zhang, Chengwu Tang ... · Cognition · Huzhou Key Laboratory of Translational Medicine, The First Affiliated Hospital of Huzhou University, The First People's Hospital of Huzhou, Huzhou, 313000, Zhejiang Province, China. · pubmed

In this study, we explored the potential application of [d-Ala2, d-Leu5]-enkephalin (DADLE) in anti-ageing field in response to the trend of increasing global population ageing. We aimed to reveal experimentally whether DADLE can positively affect the lifespan and health of aged ...

In this study, we explored the potential application of [d-Ala2, d-Leu5]-enkephalin (DADLE) in anti-ageing field in response to the trend of increasing global population ageing. We aimed to reveal experimentally whether DADLE can positively affect the lifespan and health of aged mammals through its unique anti-inflammatory or metabolic mechanisms. Forty-two female C57/BL6J mice aged 18 months were intraperitoneally injected with DADLE or normal saline for 2 months. Cognitive and motor functions were assessed using a water maze and treadmill stress test, respectively. The expressions of P16INK4A, Lamin B1 and sirtuin 1 were observed in the hippocampus and heart. The level of pro-inflammatory cytokines in the serum was measured by enzyme-linked immunosorbent assay. The telomere length of the mice was determined using the polymerase chain reaction method. Transcriptome analysis of 6-month-old female C57BL/6 J mice brains and hearts was assessed for body weight effects. Supplementation of exogenous DADLE to aged mice has demonstrated significant benefits, including improved motor function, enhanced cognitive performance and significantly extended lifespan. DADLE treatment resulted in a substantial increase in anti-ageing markers and a corresponding decrease in pro-ageing markers in the heart and brain of these mice. DADLE attenuated age-related inflammation, as evidenced by reductions in serum pro-inflammatory cytokines and inflammatory cell infiltration in tissues. Furthermore, DADLE supplementation significantly prolonged relative telomere length in aged female mice, suggesting a potential mechanism for its anti-ageing effects. Transcriptome analysis revealed that immune response and cellular signalling pathways are intricately involved in the protective effects of DADLE in aged mice, providing further insights into its mechanism of action. Inflammatory reaction may be improved by DADLE by regulating the infiltration of inflammatory cells in the liver and kidney and regulating the cognitive function of the brain and the ageing of the heart in mice.

Longevity Relevance Analysis (5)

The paper claims that DADLE treatment improves physical and cognitive function while extending lifespan in aged female mice. This research is relevant as it investigates a potential intervention that targets mechanisms of aging and inflammation, contributing to the understanding of lifespan extension and healthspan improvement.

Single-Cell Transcriptomic Analysis Identifies Senescent Osteocytes That Trigger Bone Destruction in Breast Cancer Metastasis.

Japneet Kaur, Manish Adhikari, Hayley M Sabol ... · Osteocytes · Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. · pubmed

Breast cancer bone metastases increase fracture risk and are a major cause of morbidity and mortality among women. Upon colonization by tumor cells, the bone microenvironment undergoes profound reprogramming to support cancer progression, which disrupts the balance between osteoc...

Breast cancer bone metastases increase fracture risk and are a major cause of morbidity and mortality among women. Upon colonization by tumor cells, the bone microenvironment undergoes profound reprogramming to support cancer progression, which disrupts the balance between osteoclasts and osteoblasts and leads to bone lesions. A deeper understanding of the processes mediating this reprogramming could help develop interventions for treating patients with bone metastases. Here, we demonstrated that osteocytes (Ot) in established breast cancer bone metastasis develop premature senescence and a distinctive senescence-associated secretory phenotype (SASP) that favors bone destruction. Single-cell RNA sequencing identified Ots from mice with breast cancer bone metastasis enriched in senescence, SASP markers, and pro-osteoclastogenic genes. Multiplex in situ hybridization and artificial intelligence-assisted analysis depicted Ots with senescence-associated satellite distension, telomere dysfunction, and p16Ink4a expression in mice and patients with breast cancer bone metastasis. Breast cancer cells promoted Ot senescence and enhanced their osteoclastogenic potential in in vitro and ex vivo organ cultures. Clearance of senescent cells with senolytics suppressed bone resorption and preserved bone mass in mice with breast cancer bone metastasis. These results demonstrate that Ots undergo pathological reprogramming by breast cancer cells and identify Ot senescence as an initiating event triggering lytic bone disease in breast cancer metastases. Significance: Breast cancer cells remodel the bone microenvironment by promoting premature cellular senescence and SASP in osteocytes, which can be targeted with senolytics to alleviate bone loss induced by metastatic breast cancer. See related commentary by Frieling and Lynch, p. 3917.

Longevity Relevance Analysis (5)

The paper addresses the role of senescent osteocytes in the context of breast cancer bone metastasis, highlighting a mechanism that contributes to bone destruction. By identifying senescence as a pathological process that can be targeted with senolytics, it touches on a potential intervention that could mitigate age-related bone loss and cancer progression. This aligns with longevity research by exploring cellular senescence, a key aspect of aging. However, while the findings are significant, they primarily focus on a specific disease context rather than providing broad insights into aging mechanisms, thus limiting its overall impact.