Catégorie : Blog

A team of researchers has waded into a controversial and contradictory area of study, publishing information on the link between obesity and an inflammatory molecule that increases with aging.

A context-dependent molecule

The authors point out previous research that singled out the interleukin IL-6, a key immune signaling molecule, as a major contributor to inflammaging [1]. However, its role in biology is complicated, and much of the relevant research is contradictory: it has been reported to have both pro- and anti-inflammatory functions, depending on context [2], and it plays multiple roles in metabolism [3].

Adding to this confusion, some research has found that it enhances insulin secretion in muscle tisssue [4], while other research has found that it increases insulin resistance in the liver [5]. Most importantly for this study, previous work has found that it stimulates fat burning [6]. These researchers, however, have come to the opposite conclusion: that IL-6 inhibits fat burning and promotes obesity instead.

Beginning with humans, moving on to mice

This work began by studying 77 hospitalized patients who had type 2 diabetes and were at least 65 years old. The third of this group that had the most IL-6 also had significantly more fat on their organs than the other two thirds. This was found to be true even when adjusting for many known confounders, such as age, disease length, other metabolic and diabetes biomarkers, and vascular issues.

However, those human results are only a correlation. In an attempt to prove causation, they moved to an animal model. Older wild-type mice naturally express more IL-6 than younger wild-type mice, but compared to a genetically modified model that does not express IL-6 at all, they found no significant differences in lifespan, liver function, insulin use, or glucose.

With aging, older wild-type mice also naturally gain more weight, but this weight gain was significantly blunted in mice that did not express IL-6. These modified mice also had somewhat less skin fat and far less fat around their organs, along with less cholesterol and fewer triglycerides. Wild-type mice expend less energy with age; this change, too, was significantly blunted in the IL-6-deficient mice. Gene expression analysis found that a deficiency in IL-6 meant that pathways related to fat burning were upregulated compared to the wild-type group.

A closer look discovered that, in older wild-type mice, fat cells near organs can become significantly larger than normal. This was found to be the reason why IL-6 deficiency resulted in so much less organ fat: the IL-6-deficient mice accumulated far fewer of these large fat cells.

Age-related effects in mice, but questionable for people

Most importantly, all of these differences were only found between the aged mice in each group. There were no significant differences between young mice in either group. However, as IL-6 is a core signaling molecule with well-documented effects, attempting to completely suppress IL-6 in people would be likely to do more harm than good.

These researchers suggest that the effects of IL-6 are largely cell-dependent and that these particular detrimental effects are specific to fat tissue. Biology is not fully mapped, but in this case, it is likely that a far more complete map of the true cause-and-effect biochemical relationship between interleukins and fat tissue would need to be created before this line of research could result in drug development.

Literature

[1] Gabay, C. (2006). Interleukin-6 and chronic inflammation. Arthritis research & therapy, 8, 1-6.

[2] Scheller, J., Chalaris, A., Schmidt-Arras, D., & Rose-John, S. (2011). The pro-and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1813(5), 878-888.

[3] Giraldez, M. D., Carneros, D., Garbers, C., Rose-John, S., & Bustos, M. (2021). New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology. Nature reviews Gastroenterology & hepatology, 18(11), 787-803.

[4] Ellingsgaard, H., Hauselmann, I., Schuler, B., Habib, A. M., Baggio, L. L., Meier, D. T., … & Donath, M. Y. (2011). Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nature medicine, 17(11), 1481-1489.

[5] Sabio, G., Das, M., Mora, A., Zhang, Z., Jun, J. Y., Ko, H. J., … & Davis, R. J. (2008). A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science, 322(5907), 1539-1543.

[6] Van Hall, G., Steensberg, A., Sacchetti, M., Fischer, C., Keller, C., Schjerling, P., … & Pedersen, B. K. (2003). Interleukin-6 stimulates lipolysis and fat oxidation in humans. The Journal of Clinical Endocrinology & Metabolism, 88(7), 3005-3010.

Scientists have tested a novel method of providing cells with healthy mitochondria to fight Parkinson’s disease [1].

Replacing damaged mitochondria

Parkinson’s disease is the second-most prevalent neurodegenerative disorder, and it affects 10 million people worldwide. The disease is age-related, as its prevalence rises rapidly in people older than 65, although some people are diagnosed much earlier. Parkinson’s disease is characterized by both motor and mental problems: tremor, rigidity (stiffness), and slowness of movement along with memory and thinking deficits.

Parkinson’s disease is caused by the loss of dopamine-producing (dopaminergic) neurons in a brain region called the substantia nigra. Therapeutic options are limited, and some of the existing ones cause nasty side effects.

Since Parkinson’s disease involves the dying of cells, it’s unsurprising that one of its hallmarks is mitochondrial dysfunction. It has been observed in Parkinson’s disease models in which neuronal damage is generated by toxins or genetics [2].

While some therapeutics exist that target damaged mitochondria, another approach has recently arisen: “transplanting” healthy mitochondria into the affected cells. Scientists have demonstrated that if you isolate mitochondria from various types of cells and inject them into the body, they will preferentially travel to cells and tissues with damaged mitochondria [3].

One candidate drug, PN-101, which is based on mitochondria from human umbilical cord mesenchymal stem cells (UC-MSCs), is already in advanced clinical trials for a number of indications. In this new study, the researchers investigated its therapeutic potential against Parkinson’s disease.

Healthy mitochondria for healthy neurons

First, the researchers co-incubated mitochondria from UC-MSCs with dopaminergic neuron-like cells derived from a line of precursors. It is known that cells can uptake extracellular mitochondria, and sure enough, the researchers detected the transfer of fluorescence-labeled mitochondria into the cells.

Next, the researchers tried the same trick on cells treated by various neurotoxins. The damaged cells, which resembled PD-affected neurons, showed morphological abnormalities, such as neurite degeneration. Treating them with PN-101 significantly improved the cells’ viability.

Neuroinflammation is a hallmark of Parkinson’s disease and other neurodegenerative disorders. Activated microglia, the resident immune cells of the brain, secrete various pro-inflammatory molecules, driving the disease. The researchers tested their mitochondria cocktail on a line of murine microglia treated with lipopolysaccharide, a bacteria-associated molecule that triggers inflammation. PN-101 robustly reduced the mRNA expression and/or secretion of several inflammatory markers such as IL-6 and TNF-alpha.

Bringing down motor deficits and inflammation

When the researchers administered fluorescence-labeled mitochondria to mice intravenously, they found that the mitochondria were taken up mostly by astrocytes, the main type of “maintenance” cells in the brain, rather than by dopaminergic neurons or microglia. This was surprising and at odds with the in vitro results. Despite that, PN-101 was successful in alleviating motor deficits in mice, on par with the positive control, L-DOPA (levodopa), which can cause side effects such as involuntary movements [4].

However, PN-101 was better than L-DOPA in reversing neuronal loss in a mouse toxin-induced model of Parkinson’s disease. It also alleviated microglia activation to the level of healthy controls.

Injections of mitochondria is an exciting approach that can be used far beyond Parkinson’s disease. Mitochondrial dysfunction is one of the central hallmarks of aging and affects numerous organs and tissues, probably exacerbating many other hallmarks. Replacing defective organelles might be a game changer in longevity therapies.

In this study, we demonstrated that mitochondrial transplantation ameliorated dopaminergic cell damage and neuroinflammation in vitro and in vivo. We demonstrated that exogenous fluorescence-labeled mitochondria were successfully transferred into dopaminergic neurons in vitro and astrocytes in vivo. Moreover, the results showed that isolated PN-101 mitochondria were successfully transferred into dopaminergic cells and reversed neurotoxins-induced cytotoxicity. In addition, PN-101 reduced mRNA expression and secretion of pro-inflammatory cytokines in microglial cells. Furthermore, intravenous PN-101 administration improved MPTP-induced motor declines observed in the mice model. Lastly, PN-101 treatment ameliorated dopaminergic neuronal loss and suppressed microglial activation in the brain. These results suggest that PN-101 can be a potential therapeutic treatment against PD by mediating both the neuroprotective and anti-inflammatory effects.

Literature

[1] Eo, H., Yu, S. H., Choi, Y., Kim, Y., Kang, Y. C., Lee, H., Kim, J. H., Han, K., Lee, H. K., Chang, M. Y., Oh, M. S., & Kim, C. H. (2024). Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson’s disease. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics, e00355.

[2] Bose, A., & Beal, M. F. (2016). Mitochondrial dysfunction in Parkinson’s disease. Journal of neurochemistry, 139, 216-231.

[3] Lee, S. E., Kang, Y. C., Kim, Y., Kim, S., Yu, S. H., Park, J. H., … & Kim, C. H. (2022). Preferred migration of mitochondria toward cells and tissues with mitochondrial damage. International Journal of Molecular Sciences, 23(24), 15734.

[4] Alberico, S. L., Kim, Y. C., Lence, T., & Narayanan, N. S. (2017). Axial levodopa-induced dyskinesias and neuronal activity in the dorsal striatum. Neuroscience, 343, 240-249.

A team of researchers has reported in Aging Cell that longer-lived Chinese women have less epigenetic noise in crucial areas of the genome.

Order and disorder

We have previously reported that the accumulation of epigenetic noise appears to be the main cause of epigenetic alterations. Multiple studies have reported that this noise is correlated with age-related diseases, including Alzheimer’s [1] and vascular disorders [2].

Previous work has studied this entropy in centenarians, although these studies were across the whole genome [3]. The authors of this paper decided to look closer, concluding that these longer-lived people protect certain critical gene areas against noise accumulation.

Less noise, both overall and in crucial places

These researchers used samples from a younger group of 34 people aged 45-70, an elder group of 20 people at least 70 years old, and 79 long-lived individuals (LLIs) who were, at the least, nonagenerians: people at least 90 years old. While the overall methylation entropy increased with age in the first two groups, the long-lived individuals had entropy that was generally more like the younger group: people 40 years younger than themselves. The detailed results suggested that this was broadly true across the genes in general.

Among 1842 genes deemed to be essential, the results were even more striking. The LLIs actually had more methylation entropy in nonessential genes than the “elder” group but significantly less entropy among essential genes, although there was a substantial variance within the LLIs.

Further work noted that the better-protected genes are disproportionately gene promoters, which are primarily responsible for RNA transcription. In total, 32.1% of areas were found to have less methylation entropy in LLIs than in the “elder” group. These genes were strongly associated with age-related disorders, including stroke and chronic obstructive pulmonary disorder (COPD). Cancer-related and DNA repair pathways were also represented.

Is there something special about neutrophils?

Neutrophils are the most common kind of blood cell and are responsible for defending against infection. A full 43.1% of the protected regions applied to specific cell types, and neutrophil-related genes were 97.3% of ths group, even though LLIs did not have a significant difference in the number of neutrophils compared to the “elder” group. They did, however, have significantly fewer B cells and CD4+ T cells. The genes that were specific to neutrophils were found to be related to Parkinson’s disease, diabetic cardiomyopathy, and core aspects of proteostasis.

Previous research has suggested that age-related neutrophil changes may make strokes more dangerous [4], and a research team including Steve Horvath has found that neutrophil epigenetic age is particularly connected with Parkinson’s [5]. These researchers hypothesize that the epigenetic protection of these cells in particular is protecting LLIs from age-related diseases, although the details are not yet known.

The researchers note that these results may be only applicable to women. Very long-lived men are considerably rarer than very long-lived women, and they were not available to be part of this cohort. Further studies will need to be conducted to determine if these results are sex-specific.

Literature

[1] Levy, O., Amit, G., Vaknin, D., Snir, T., Efroni, S., Castaldi, P., … & Bashan, A. (2020). Age-related loss of gene-to-gene transcriptional coordination among single cells. Nature metabolism, 2(11), 1305-1315.

[2] Zhang, W., Zhang, S., Yan, P., Ren, J., Song, M., Li, J., … & Qu, J. (2020). A single-cell transcriptomic landscape of primate arterial aging. Nature communications, 11(1), 2202.

[3] Heyn, H., Li, N., Ferreira, H. J., Moran, S., Pisano, D. G., Gomez, A., … & Esteller, M. (2012). Distinct DNA methylomes of newborns and centenarians. Proceedings of the National Academy of Sciences, 109(26), 10522-10527.

[4] Gullotta, G. S., De Feo, D., Friebel, E., Semerano, A., Scotti, G. M., Bergamaschi, A., … & Bacigaluppi, M. (2023). Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology. Nature Immunology, 24(6), 925-940.

[5] Horvath, S., & Ritz, B. R. (2015). Increased epigenetic age and granulocyte counts in the blood of Parkinson’s disease patients. Aging (Albany NY), 7(12), 1130.