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Category: life extension

Genome-wide association study of proteomic aging reveals shared genetic architectures with longevity, early life development, and age-related diseases

There is still relatively little known about the genetic underpinnings of proteomic aging clocks. Here, we describe a genome-wide association study of proteomic aging in the UK Biobank (n=38,865), identifying 27 loci associated with participants’ proteomic age gap (ProtAgeGap). ProtAgeGap exhibits a strong genetic correlation with longevity (rg = −0.83), and in FinnGen a ProtAgeGap polygenic score (PGS) was associated with significantly increased odds of achieving longevity (n=500,348; OR = 1.43). Additional PGS analyses in All of Us (n=117,415), China Kadoorie Biobank (n=100,640), and ABCD Study (n=5,204) demonstrate reproducible associations across biobanks of ProtAgeGap PGS with obesity, cardiometabolic disease, and osteoarthritis in adults, and with developmental timing in children. Finally, colocalization analysis identified FTO as an obesity-related mechanism uniting diverse aging traits. Our results demonstrate a shared genetic architecture across the life course of ProtAgeGap with longevity, early developmental biology, and cardiometabolic and musculoskeletal diseases.

### Competing Interest Statement.

The authors have declared no competing interest.

Rejuvenating aged haematopoietic stem cells by targeting RhoA

In their nucleus, as they replicate, blood stem cells can accumulate mutations and lose epigenetic marks that used to keep DNA well-arranged, ultimately increasing mechanical tension on the nuclear envelope. This study figured out RhoA is a mechanosensor activated by such tension and conducts a key role in the stem cell ageing process. Researchers subsequently proved its rejuvenating potential: after ex vivo treatment of blood stem cells with the drug Rhosin, a RhoA inhibitor, they observed an improvement in aged-related markers.

As study co-author summarizes: “Overall, our experiments show that Rhosin did rejuvenate blood stem cells, increased the regenerative capacity of the immune system and improved the production of blood cells once transplanted in the bone marrow.”

Ageing is defined as the deterioration of function overtime, and it is one of the main risk factors for numerous chronic diseases. Although ageing is a complex phenomenon affecting the whole organism, it is proved that the solely manifestation of ageing in the haematopoietic system affects the whole organism.

A research team previously revealed the significancy of using blood stem cells to pharmacologically target ageing of the whole body, thereby suggesting rejuvenating strategies that could extend healthspan and lifespan. Now, in a Nature Ageing publication, they propose rejuvenating aged blood stem cells by treating them with the drug Rhosin, a small molecule that inhibits RhoA, a protein that is highly activated in aged haematopoietic stem cells. This study combined in vivo and in vitro assays together with innovative machine learning techniques.

Blood stem cells, or hematopoietic stem cells, are located in the bone marrow, a highly dynamic and specialised tissue within the cavity of long bones. They are responsible for the vital function of continuously producing all types of blood cells: red blood cells (oxygen transporters), megakaryocytes (future platelets) and white blood cells (immune cells, lymphocytes and macrophages). Over time, however, stem cells also do age, they lose their regenerative capacity and generate fewer and lower quality immune cells. This has been linked to immunosenescence, chronic low grade inflammation and certain chronic diseases.

Reversing aging in blood stem cells by targeting lysosomal dysfunction

As people age, these cells become defective and lose their ability to renew and repair the blood system, decreasing the body’s ability to fight infections as seen in older adults. Another example is a condition called clonal hematopoiesis; this asymptomatic condition is considered a premalignant state that increases the risk of developing blood cancers and other inflammatory disorders. Its prevalence increases significantly with age.

The team discovered that lysosomes in aged HSCs become hyper-acidic, depleted, damaged, and abnormally activated, disrupting the cells’ metabolic and epigenetic stability. Using single-cell transcriptomics and stringent functional assays, the researchers found that suppressing this hyperactivation with a specific vacuolar ATPase inhibitor restored lysosomal integrity and blood-forming stem cell function.

The old stem cells started acting young and healthy once more. Old stem cells regained their regenerative potential and ability to be transplanted and to produce more healthy stem cells and blood that is balanced in immune cells; they renewed their metabolism and mitochondrial function, improved their epigenome, reduced their inflammation, and stopped sending out “inflammation” signals that can cause damage in the body.

Remarkably, ex vivo treatment (when cells are removed from the body, modified in a laboratory, and returned to the body) of old stem cells with the lysosomal inhibitor boosted their in vivo blood-forming capacity more than eightfold, demonstrating that correcting lysosomal dysfunction can restore regenerative potential.

This restoration also dampened harmful inflammatory and interferon-driven pathways by improving lysosomal processing of mitochondrial DNA and reducing activation of the cGAS-STING immune signaling pathway, which they find to be a key driver of inflammation and aging of stem cells.

Researchers have discovered how to reverse aging in blood-forming stem cells in mice by correcting defects in the stem cell’s lysosomes. The breakthrough, published in Cell Stem Cell, identifies lysosomal hyperactivation and dysfunction as key drivers of stem cell aging and shows that restoring lysosomal slow degradation can revitalize aged stem cells and enhance their regenerative capacity.

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Comparative analysis of human and mouse ovaries across age

The mouse is a tractable model for human ovarian biology; however, its utility is limited by incomplete understanding of how transcription and signaling differ interspecifically and with age. We compared ovaries between species using three-dimensional imaging, single-cell transcriptomics, and functional studies. In mice, we mapped declining follicle numbers and oocyte competence during aging; in human ovaries, we identified cortical follicle pockets and decreases in density. Oocytes had species-specific gene expression patterns during growth that converged toward maturity. Age-related transcriptional changes were greater in oocytes than in granulosa cells across species, although mature oocytes change more in humans. We identified ovarian sympathetic nerves and glia; axon density increased in aged ovaries and, when ablated in mice, perturbed folliculogenesis.

New Discovery: This Molecule Could Beat Rapamycin in Longevity

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Dive into the future of longevity research with Dr. Ben Blue, CEO of Ora Biomedical. We explore how Ora’s high-throughput “Wormbot” platform is conducting the world’s largest unbiased search for longevity interventions, moving beyond the narrow focus on established pathways like mTOR.

In this episode, we discuss:
• The ambitious Million Molecule Challenge and why it could revolutionize the field.
• Surprising discoveries already made, including molecules that outperform rapamycin.
• Ora’s strategic pivot to radiation resistance, with applications for astronauts, pilots, and human health.
• How their data-driven approach is uncovering interventions for resilience against toxins and other stresses.
• The journey from worm models to potential clinical trials and what’s next for the company.

Learn how Ora is scaling drug discovery to tackle aging and age-related diseases.

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https://www.linkedin.com/company/ora-biomedical-inc/

This video was produced by One Billion Media, an agency that specializes in YouTube virality for health brands and experts. Learn more about their work here:

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Role of ubiquilin-2 liquid droplets in α-synuclein aggregation

Parkinson’s disease (PD) is an age-related, progressive neurodegenerative disorder. The hallmark of PD pathogenesis is the Lewy bodies (LBs) that accumulate in neurons in the substantia nigra region of the brain, damaging these neurons and leading to the motor symptoms of the disease. α-synuclein (α-syn), a misfolded protein, aggregates and forms fibrils, which leads to the formation of LBs. The exact molecular mechanism behind this aggregation process is yet to be uncovered. With an increasing number of elderly patients suffering from Parkinson’s and other neurodegenerative diseases worldwide, it is important to understand the aggregation process, find potential therapeutic targets to mitigate or inhibit the aggregation, and slow down the disease progression.

Liquid-liquid phase separation (LLPS), a process where a uniform mixture spontaneously divides into two liquid phases with differing component concentrations, is often considered the reason behind α-syn aggregation. Even though LLPS of α-syn was previously reported, the question remains: are they involved in catalyzing the early stage of aggregation? Ubiquilin-2 (UBQLN2) protein, mainly involved in maintaining protein homeostasis, also undergoes LLPS under certain physiological conditions. Interestingly, it is known to be associated with several neurodegenerative diseases.

Are liquid droplets formed by UBQLN2 catalyzing the α-syn protein aggregation? A team of researchers decided to unravel the involvement of UBQLN2 in α-syn aggregation and fibril formation. “By uncovering the mechanisms that trigger the aggregation process, we hope to find new ways to prevent it and ultimately contribute to the development of disease-modifying treatments,” mentioned the senior author of the study. The study was published in The EMBO Journal.

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