Mois : juillet 2024

In Aging, a pair of researchers has published a perspective connecting fat (lipid) accumulation and cellular senescence in neurons to Parkinson’s disease.

α-syn, but not just α-syn

Parkinson’s disease is characterized by the loss of a specific population of neurons: the dopaminergic neurons in the substantia nigra, a part of the brain that governs movement [1]. The ensuing problems with basic movement are accompanied by cognitive decline and depression.

At the cellular level, a key hallmark is the accumulation of alpha-synuclein (α-syn) aggregates that lead to Lewy bodies. This is connected to lipid metabolism, and research has found that stressors that encourage Parkinson’s disease also encourage lipid accumulation [2]. Aging is, of course, the strongest risk factor for Parkinson’s, but genetic factors also play a role: the most well-documented of these is a mutation of GBA, a gene that encodes for β-glucocerebrosidase (GCase), an enzyme that breaks down glucosylceramides (GluCer), a class of lipids.

This relationship appears to be a strong one: increased amounts of GluCer are associated with sharp cognitive decline in Parkinson’s patients, and a lack of GCase appears to be the cause [3]. Dysfunction of the lysosomes [4], which break down protein, and reactions with dopamine itself [5] may also contribute to this increase in GluCer.

The genetic link

These researchers had found that this is also connected to cellular senescence [6]. SATB1, a gene that has also been found to be a risk factor for Parkinson’s, downregulates the microRNA miR-22-3p, which downregulates GBA. Therefore, a reduction in SATB1 leads to more GluCer and senescence in the neurons. In that paper, these researchers had treated human neurons with GluCer and found that it drove them senescent and encouraged α-syn aggregation. A previous paper had also found that lipid droplet accumulation and cellular senescence are connected [7].

This connection between lipid droplets and senescence also appears to involve α-syn. Lipid droplets themselves encourage its production, and α-syn by itself has been found to drive the relevant cells senescent [8]. The researchers note that this may be dependent on cell type: a reduction in SATB1 drives dopaminergic neurons, which are specifically harmed by Parkinson’s disease, senescent [9], while it does not drive other types of neurons senescent. These neurons, in particular, are dependent on the function of lysosomes.

This difference in specific cell type appears to be why Parkinson’s is limited to such a small and critical population of neurons. Most critically, it gives researchers a potential new target for Parkinson’s therapies. If GBA or lipid accumulation can be directly affected in addition to α-syn, it might be possible for Parkinson’s disease to be treated much more effectively.

Literature

[1] Dauer, W., & Przedborski, S. (2003). Parkinson’s disease: mechanisms and models. Neuron, 39(6), 889-909.

[2] Alecu, I., & Bennett, S. A. (2019). Dysregulated lipid metabolism and its role in α-synucleinopathy in Parkinson’s disease. Frontiers in neuroscience, 13, 328.

[3] Huh, Y. E., Park, H., Chiang, M. S. R., Tuncali, I., Liu, G., Locascio, J. J., … & Scherzer, C. R. (2021). Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI. npj Parkinson’s Disease, 7(1), 102.

[4] Arévalo, N. B., Lamaizon, C. M., Cavieres, V. A., Burgos, P. V., Álvarez, A. R., Yañez, M. J., & Zanlungo, S. (2022). Neuronopathic Gaucher disease: Beyond lysosomal dysfunction. Frontiers in Molecular Neuroscience, 15, 934820.

[5] Riessland, M., Kolisnyk, B., & Greengard, P. (2017). Reactive dopamine leads to triple trouble in nigral neurons. Biochemistry, 56(49), 6409-6410.

[6] Russo, T., Kolisnyk, B., BS, A., Plessis‐Belair, J., Kim, T. W., Martin, J., … & Riessland, M. (2024). The SATB1‐MIR22‐GBA axis mediates glucocerebroside accumulation inducing a cellular senescence‐like phenotype in dopaminergic neurons. Aging cell, 23(4), e14077.

[7] Millner, A., & Atilla-Gokcumen, G. E. Lipid Players of Cellular Senescence. Metabolites 2020, 10, 339.

[8] Verma, D. K., Seo, B. A., Ghosh, A., Ma, S. X., Hernandez-Quijada, K., Andersen, J. K., … & Kim, Y. H. (2021). Alpha-synuclein preformed fibrils induce cellular senescence in Parkinson’s disease models. Cells, 10(7), 1694.

[9] Riessland, M., Kolisnyk, B., Kim, T. W., Cheng, J., Ni, J., Pearson, J. A., … & Greengard, P. (2019). Loss of SATB1 induces p21-dependent cellular senescence in post-mitotic dopaminergic neurons. Cell stem cell, 25(4), 514-530.

Today, Rejuve.AI, the world’s first decentralized AI longevity research network, has announced four new partnerships, bringing the grand total to 20 organizations that have committed alongside Rejuve.AI to help humankind live longer.

Rejuve.AI is working to lengthen lifespans by paying members in its RJV crypto token to share their own health data to help shed light on how we can help humanity live longer. This democratization of data allows scientists to make recommendations based on a wider set of information.

To further this, Rejuve.AI has now onboarded OpenCures, an organization that accelerates the development of health technologies through collaboration, alongside NoAGE, an innovative supplement helping people to reverse the effects of aging, plus DNA Longevity, a telehealth genetic counseling services and Erbology, a business that searches the world for the finest plant-based ingredients to create functional foods with that feel good factor. They join a number of existing, committed partners, including Purovitalis.

With partners now signed on in eight countries, Rejuve.AI is nearly ready to launch its Longevity App and start contributing to wider health research. These partnerships allow the organization to appeal to as wide an audience as possible to gather the data sets longevity scientists need for research, as well as give personalized insights to those who share data. This is because once health data has been gathered and shared with Rejuve.AI, the user will be paid in the organization’s RJV crypto token which can be used to buy products across a number of token partners, so the more partners, the larger the appeal to users.

CEO of OpenCures Dr. Kevin Perrott stated “Rejuve.AI not only has the models, but it also has the commitment over the years to the understanding of healthy longevity and the interest in increasing lifespan that most AI-based entities do not have. Having Rejuve.AI as a partner, one that understands that we are in it for the long haul, helps build the stable ecosystem that we need to co-create to minimize time to the development of interventions.”

Alongside onboarding more partners, Rejuve.AI, specifically the DataNFT contract, was also recently audited by HACKEN, an international cybersecurity company. This audit showed incredibly positive results ahead of the app launch. Only low-severity issues were identified which the team can now work to fix ahead of the formal launch later in the year.

The launch of this app, later in 2024, is set to be industry-changing, as there is nothing similar in either the health or crypto sectors. By harnessing the disruptive nature of crypto, Rejuve.AI is able to breathe new life into longevity.

Jasmine Smith, CEO of Rejuve.AI stated, “Our partners make what we do possible. It’s incredibly important we continue building a wide network of collaborators who are as passionate as us about longevity research. Bringing together our joint knowledge and utilizing one another where possible is key to building out longevity research. I look forward to the work we’ll do with these partners this year, and for years to come, as we all come together to help humanity live longer.”

If you are interested in learning more about Rejuve.AI’s Longevity App and how it will be used to contribute to health, longevity and wellbeing research, please see more here: https://www.rejuve.ai/longevity-app

About Rejuve.AI

Rejuve.AI, the world’s first decentralized AI longevity research network, brings together blockchain, artificial intelligence, and cutting-edge longevity research. With a firm belief that an enhanced, healthy lifespan shouldn’t be an elite privilege, Rejuve.AI promotes equitable access to longevity benefits.

Users contribute health data via the Longevity app on iOS and Android, earning RJV tokens in return. These tokens unlock a wealth of wellness products and personalized longevity insights.

Central to Rejuve.AI is its unique tokenomic model, encompassing both the RJV utility token and innovative non-fungible tokens (NFTs) – the Data NFT (dNFT) and the Product NFT (pNFT). This structure guarantees a fair reward system for all contributors.

Beyond its platform, Rejuve.AI is carving out strategic partnerships across the longevity ecosystem, from supplement providers to biopharma companies, amplifying its impact.

In essence, Rejuve.AI isn’t just a platform—it’s a movement. Merging the technological promise of Web3 with the age-old quest for longevity, Rejuve.AI envisions a world where healthy aging is democratically accessible to all.

Research published in Aging Cell has revealed that a nematode species commonly used for aging research lives much longer on an alternate-day fasting regimen, but only when it is administered in middle age and only when the worms are consuming an animal-based protein source.

Deciding what to restrict and when

Dietary restriction practices have been broadly reported as being beneficial for health [1]. Some of these focus on restricting calories over time, while others restrict when food can be taken in at all. Alternative-day fasting, which limits food intake to every other day, is one of the most stark forms, and it has been previously reported to lengthen the lifespan of C.elegans, a roundworm that is commonly used in longevity experiments [2].

While the biological mechanisms of dietary restriction have been explored, there are still questions remaining as to how it relates to aging and the role of protein restriction, and protein sources, in this sort of intervention [3]. To answer them, these researchers studied C.elegans with a focus on the lysomes, the cellular organelles responsible for breaking down proteins.

Strong benefitss in a single population

In this experiment, the researchers began alternate-day fasting (ADF) at three different time periods in these worms’ lives, with either plant-based or animal-based food sources. Young worms suffered badly from ADF: egg-laying was greatly impaired, with eggs hatching inside the worms. Even when a sterile strain was used, early-life ADF caused dramatic decreases in lifespan. Examination of the specific genes involved suggested that fundamental developmental pathways were being harmed.

On the other hand, ADF greatly lengthened the lives of middle-aged worms that were fed animal-based protein solution instead of a plant-based one. This finding is surprising, as C.elegans‘ lifespan is only moderately lengthened by feeding the worms plant-based instead of animal-based protein sources. Additionally, beginning ADF in worms near the end of their lifespans yielded no benefit.

These results were found to be due to the upregulation of cpr-2 and cpr-5, two genes related to lysosomal function. In C.elegans, lysosomes grow long tubes with aging, decrease in acidity, and decrease in number; however, ADF restricted this lengthening and helped the worms retain more lysosomes with the proper acidity. This lysosomal protection and lifespan extension was counteracted when genetic or other interventions were used to block these genes or their downstream effects, showing that they indeed were the cause. Once more, these effects were only in worms fed animal protein; ADF had no measurable effects on worms fed plant-based proteins.

While it did not affect cells’ self-consumption of damaged organelles (autophagy), ADF had notable positive effects on fat consumption (lipophagy) and the clearance of aggregated proteins. As aggregated proteins are a fundamental aspect of aging and are core to such crippling brain diseases as Alzheimer’s and Parkinson’s, the researchers closely examined model worms for their ability to deal with the key proteins involved. Once more, ADF was found to have beneficial effects in clearing out these dangerous aggregates, but again, these effects only occurred in worms fed animal-based protein.

These findings will take considerably more work to apply to other animals, including human beings. These experiments demonstrated the effectiveness of fasting every other day in a worm that usually lives for less than a month. Furthermore, the researchers could not ascertain exactly why ADF only showed measurable effects in worms fed animal-based protein; a careful assessment of lysosomal protein relationships will be needed to determine why this is the case.

Literature

[1] Longo, V. D., Di Tano, M., Mattson, M. P., & Guidi, N. (2021). Intermittent and periodic fasting, longevity and disease. Nature aging, 1(1), 47-59.

[2] Honjoh, S., Yamamoto, T., Uno, M., & Nishida, E. (2009). Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans. Nature, 457(7230), 726-730.

[3] Solon-Biet, S. M., Mitchell, S. J., Coogan, S. C., Cogger, V. C., Gokarn, R., McMahon, A. C., … & Le Couteur, D. G. (2015). Dietary protein to carbohydrate ratio and caloric restriction: comparing metabolic outcomes in mice. Cell reports, 11(10), 1529-1534.