Combination Gene Therapy for α-Klotho and TGFβR2 Improves Osteoarthritis in Mice

Researchers here report that upregulation of α-Klotho and TGFβR2 together, via gene therapy, can modestly reverse osteoarthritis in a rat model in which untreated animals progress to a more severe stage of the condition. Inhibiting TGF-β receptors such as TGFβR2 is known to suppress chronic inflammation, and likely functions by interfering in the inflammatory TGF-β signaling produced by senescent cells. The evidence for cellular senescence to drive the progression of osteoarthritis is quite compelling at this point. Meanwhile, α-Klotho declines with age and upregulation of this protein is known to improve regenerative capacity in some tissues. Osteoarthritis is caused by gradual changes to cartilage that cushions bones and joints. During aging and repetitive stress, molecules and genes in the cells of this articular cartilage change, eventually leading to the breakdown of the cartilage and the overgrowth of underlying bone, causing chronic pain and stiffness. Previous research had pinpointed two molecules, αKLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs to treat osteoarthritis. αKLOTHO acts on the mesh of molecules surrounding articular cartilage cells, keeping this extracellular matrix from degrading. TGFβR2 acts more directly on cartilage cells, stimulating their proliferation and preventing their breakdown. Researchers treated young, otherwise healthy rats with osteoarthritis with viral part...
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In conclusion, this study suggests that epigenetic age acceleration is significantly associated with lung function in women older than 50 years. We hypothesised that this could be due to menopause. However, we have observed that menopause has minimal effect and therefore there is possibility of other unknown physiological factors at older age in females mediating the epigenetic age acceleration effect on lung function. While, it is still unknown what exactly epigenetic aging from DNA methylation measures, this study suggests it can be utilised as one of the important factors to assess women's lung health in old age. DNA me...
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This study elucidates the potential to use mitochondria from different donors (PAMM) to treat UVR stress and possibly other types of damage or metabolic malfunctions in cells, resulting in not only in-vitro but also ex-vivo applications. Gene Therapy in Mice Alters the Balance of Macrophage Phenotypes to Slow Atherosclerosis Progression https://www.fightaging.org/archives/2019/07/gene-therapy-in-mice-alters-the-balance-of-macrophage-phenotypes-to-slow-atherosclerosis-progression/ Atherosclerosis causes a sizable fraction of all deaths in our species. It is the generation of fatty deposits in blood vessel...
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Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more. This content is...
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In this study, we found that senescent chondrocytes isolated from OA patients secrete more EVs compared with nonsenescent chondrocytes. These EVs inhibit cartilage ECM deposition by healthy chondrocytes and can induce a senescent state in nearby cells. We profiled the miR and protein content of EVs isolated from the synovial fluid of OA joints from mice with SnCs. After treatment with a molecule to remove SnCs, termed a senolytic, the composition of EV-associated miR and protein was markedly altered. The senolytic reduced OA development and enhanced chondrogenesis, and these were attributable to several specific differenti...
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In conclusion, long-term aerobic exercise appears to attenuate the decline in endothelial vascular function, a benefit which is maintained during chronological aging. However, currently there is not enough evidence to suggest that exercise interventions improve vascular function in previously sedentary healthy older adults. Hijacking the Proteasome to Dispose of Unwanted Molecules in Age-Related Disease https://www.fightaging.org/archives/2019/03/hijacking-the-proteasome-to-dispose-of-unwanted-molecules-in-age-related-disease/ Cells are equipped with a protein disposal system in the form of the proteaso...
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This study demonstrates that small peptide domains derived from native protein amelogenin can be utilized to construct a mineral layer on damaged human enamel in vitro. Six groups were prepared to carry out remineralization on artificially created lesions on enamel: (1) no treatment, (2) Ca2+ and PO43- only, (3) 1100 ppm fluoride (F), (4) 20 000 ppm F, (5) 1100 ppm F and peptide, and (6) peptide alone. While the 1100 ppm F sample (indicative of common F content of toothpaste for homecare) did not deliver F to the thinly deposited mineral layer, high F test sample (indicative of clinical varnish treatment) formed mainly C...
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We present concepts of the immune response to tissue trauma as well as the interactions with SnCs and the local tissue environment. Finally, we discuss therapeutic implications of targeting SnCs in treating osteoarthritis.
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This study didn't measure whether receiving the cardiosphere-derived cells extended lifespans, so we have a lot more work to do. We have much to study, including whether CDCs need to come from a young donor to have the same rejuvenating effects and whether the extracellular vesicles are able to reproduce all the rejuvenating effects we detect with CDCs." Cardiac and systemic rejuvenation after cardiosphere-derived cell therapy in senescent rats Cardiosphere-derived cell (CDC) therapy has exhibited several favourable effects on heart structure and function in humans and in preclinical models; however,...
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In conclusion, documentation is important, a critical part of advocacy and the development process at the larger scale. It isn't just words, but rather a vital structural flow of information from one part of the larger community to another, necessary to sustain progress in any complex field. We would all do well to remember this - and to see that building this documentation is an activity in which we can all pitch in to help. Evidence Suggests that, at Least in Earlier Stages, Alzheimer's Disease Blocks Rather than Destroys Memories https://www.fightaging.org/archives/2017/07/evidence-suggests-that-at-least-in-ea...
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In this study we demonstrate the use of clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing to alter cell response to inflammatory environments by repressing inflammatory cytokine cell receptors, specifically TNFR1 and IL1R1. This has applications for many inflammatory-driven diseases. It could be applied for arthritis or to therapeutic cells that are being delivered to inflammatory environments that need to be protected from inflammation." In chronic back pain, for example, slipped or herniated discs are a result of damaged tissue when inflammation causes cells to create ...
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