Mois : juin 2024

Researchers have discovered a protein that is necessary for proper healing of damaged corneal tissue and that this protein decreases with age.

Repairing a shield that is easy to damage

The corneal epithelium covers the cornea, which focuses light onto the retina of the eye. Although it fulfills multiple protective functions, this tissue is not particularly thick and is susceptible to damage [1]. Therefore, it is regularly renewed by limbal stem cells (LSCs), a population of stem cells deep in the cornea [2].

However, alongside a long list of other negative changes, the niche of these cells diminishes with aging [3]. If these cells cannot go to a damaged area and properly heal it in time, keratocytes will appear in the area and cause scarring [4].

Because the eyes of humans and smaller mammals are somewhat different, eye experiments often need to be performed in animals that are evolutionarily closer to us. Therefore, alongside human corneal tissue donations and mice, these researchers used long-tailed macaques, non-human primates that are frequently used for these sorts of experiments.

A single gene and protein

In their first experiment, the researchers scraped half of the corneal epithelium of one eye of both young and elderly macaques, then observed their healing. Within three days, the younger group was well on its way to healing, while the older group was not. By day six, the younger group had completely healed, but older monkeys took twice as much time. Unlike the younger monkeys, the older monkeys had fibroblasts in the area along with increased corneal opacity after the injury, demonstrating imperfect healing with scar tissue. These results were also found to be true in mice.

RNA transcription in younger and older LSCs was similar in uninjured tissue. However, after injury, they reacted significantly differently, with expressions related to repair and proliferation being far more upregulated in younger tissue. One of these genes coded for the SECTM1 protein, which had considerably greater expression in young corneas after wounding.

Encouraged by this discovery, the researchers then tested the effects of SECTM1 on LSCs. LSCs unable to express SECTM1 were greatly restricted in proliferation, although it did not affect their fundamental nature as stem cells. Applying extra SECTM1 to LSCs encouraged their proliferation, with greater doses having more effect. This was found to affect downstream genes, notably CDCA7, which is a critical part of the cell cycle.

The researchers then returned to animal experiments. Mice that were given anti-SECTM1 treatment experienced delayed corneal repair, while giving SECTM1 to older mice and macaques dramatically sped up their repair. In mice, it was found to make the corneas less opaque after healing was complete.

Notably, this treatment is a topical solution that could, in theory, be used in eyedrops or creams. However, the mechanism of action and potential side effects are not yet completely understood, and further studies will need to be performed before this could be clinically available for patients.

Literature

[1] Bashir, H., Seykora, J. T., & Lee, V. (2017). Invisible shield: review of the corneal epithelium as a barrier to UV radiation, pathogens, and other environmental stimuli. Journal of ophthalmic & vision research, 12(3), 305.

[2] Gonzalez, G., Sasamoto, Y., Ksander, B. R., Frank, M. H., & Frank, N. Y. (2018). Limbal stem cells: identity, developmental origin, and therapeutic potential. Wiley Interdisciplinary Reviews: Developmental Biology, 7(2), e303.

[3] Notara, M., Shortt, A. J., O’Callaghan, A. R., & Daniels, J. T. (2013). The impact of age on the physical and cellular properties of the human limbal stem cell niche. Age, 35, 289-300.

[4] Shu, D. Y., & Lovicu, F. J. (2017). Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis. Progress in retinal and eye research, 60, 44-65.

In Aging Cell, researchers have published data on a causal link between brain structure changes and age-related muscle loss (sarcopenia).

Not just falls and frailty

Sarcopenia is a key reason for the loss of independence among older people. Data on the prevalence of this gradual disorder varies by region and measurement, but some data suggests that one in twenty to one in four people over 65 in Asia may have it [1], and it is much more common in nursing homes [2].

Previous work has linked cognitive decline to sarcopenia [3, 4], which should be no surprise given that the disorders are rooted in fundamental aspects of aging. However, this work was cross-sectional and compared different people, making it impossible to prove a causal relationship. According to the authors of this paper, it isn’t just that sarcopenia and cognitive decline have the same fundamental causes: the two are causally linked.

To prove it, they relied on Mendelian randomization, a data processing technique that is well-equipped for the purpose [5]. They used this technique in both directions, looking to see how much the muscles affect the brain and vice versa.

Putting together the dataset

For brain data, the researchers used a genome-wide association set (GWAS) of 33,224 UK Biobank participants, and constructed 1,325 brain imaging structure phenotypes based on this data. These phenotypes were divide into cortical and whole-brain aspects of tissue thickness and volume.

There is no GWAS for sarcopenia by itself. However, there are GWASes for grip strength, walking pace, and appendicular lean mass, all of which have strong, fundamental associations with sarcopenia. These studies were also based on UK Biobank data, with the lean mass study including data from nearly half a million people.

In a specialized single-trait analysis study, some of the correlations that the researchers were looking for did not exist. For example, there was no significant relationship between either hand’s grip strength and brain imaging, according to this analysis’s very high threshold necessary for statistical significance. However, this analysis did find significant relationships between phenotypes of lean mass and walking speed.

The researchers then turned to a different form of analysis looking for causal relationships. Here, handgrip strength was found to be significantly affected by certain brain regions, with several phenotypes having effects on grip strength in both hands and others having effects on only one hand or the other. Walking speed was also affected by other regions, and interestingly, larger volume in one cortical region was found to be associated with slower walking. The results were similar for lean mass, with 27 phenotypes being found to have a connection.

The authors were unable to explain some of these results. However, some of them have a clear association: the explained reason for some of the handgrip strength and lean mass losses is that some of the parts of the brain responsible for motor function deteriorate with age. Therefore, as the brain becomes less able to support the body, the body’s deterioration is accelerated as well.

Fortunately for some people with frailty, this study also showed a lack of any reverse causality: muscle deterioration, at least according to these researchers, does not directly lead to brain loss.

Literature

[1] Chen, L. K., Woo, J., Assantachai, P., Auyeung, T. W., Chou, M. Y., Iijima, K., … & Arai, H. (2020). Asian Working Group for Sarcopenia: 2019 consensus update on sarcopenia diagnosis and treatment. Journal of the American Medical Directors Association, 21(3), 300-307.

[2] Cruz-Jentoft, A. J., Bahat, G., Bauer, J., Boirie, Y., Bruyère, O., Cederholm, T., … & Zamboni, M. (2019). Sarcopenia: revised European consensus on definition and diagnosis. Age and ageing, 48(1), 16-31.

[3] Osawa, Y., Tian, Q., An, Y., Studenski, S. A., Resnick, S. M., & Ferrucci, L. (2021). Longitudinal associations between brain volume and knee extension peak torque. The Journals of Gerontology: Series A, 76(2), 286-290.

[4] Gurholt, T. P., Borda, M. G., Parker, N., Fominykh, V., Kjelkenes, R., Linge, J., … & Andreassen, O. A. (2024). Linking sarcopenia, brain structure and cognitive performance: a large-scale UK Biobank study. Brain Communications, 6(2), fcae083.

[5] Hemani, G., Zheng, J., Elsworth, B., Wade, K. H., Haberland, V., Baird, D., … & Haycock, P. C. (2018). The MR-Base platform supports systematic causal inference across the human phenome. elife, 7, e34408.

In a randomized, controlled trial in humans, scientists have demonstrated that a multimodal lifestyle intervention consisting of a vegan diet, exercise, supplements, and stress management can improve the symptoms of Alzheimer’s [1].

Can we roll it back?

Despite billions of dollars invested in finding a cure for Alzheimer’s disease (AD), progress has been frustratingly slow. The current standard of pharmaceutical care can only slightly slow the progression of the disease while also causing harsh side effects.

Lifestyle modifications can have a profound impact on health, including decreasing the risk of getting Alzheimer’s. For example, the Lancet commission on dementia prevention, intervention, and care estimates that 12 potentially modifiable risk factors together account for about 40% of the world dementia burden [2].

However, it has been unclear if lifestyle interventions can help people who already have the disease. The research into this has been scant, which makes this new randomized controlled Phase 2 trial done by scientists from the UCSF, UCSD, Harvard Medical School, and Duke University all the more important.

The trial was of a moderate size, with 51 AD patients divided between the treatment group and the control group. The treatment group received a 20-week multimodal lifestyle intervention that included diet, exercise, stress management, and several supplements.

In two earlier trials, the same program led to regression of coronary atherosclerosis [3], which the authors tout as an unprecedented result: “Until then,” they write, “it was believed that coronary heart disease progression could only be slowed, not stopped or reversed, similar to how MCI (mild cognitive impairment) or early dementia due to AD are viewed today.”

This study’s length was on the shorter side, but the researchers offer an interesting explanation for that. In these studies, participants in the control group are aware that they are not receiving the intervention and the accompanying health benefits; it is impossible to have a placebo control. However, it is highly important that the control group does not change their lifestyle for the whole duration of the experiment.

In the researchers’ previous experience, 20 weeks was the longest a control group could reliably go on without starting to spontaneously improve their own lifestyle. In compensation, the control group was offered the same intervention course after the experiment free of charge. Both groups continued to receive their usual AD-related care.

Diet, exercise, yoga

The intervention program was built upon several pillars, starting with a wholesome, minimally processed vegan diet that is high in complex carbohydrates (predominantly fruits, vegetables, whole grains, legumes, soy products, seeds, and nuts) and low in harmful fats, sweeteners, and refined carbohydrates. 14-18% of calories came from fat, 16-18% from protein, and 63-68% from mostly complex carbohydrates. Caloric intake was unrestricted.

The exercise routine included aerobic physical activity such as walking for at least 30 minutes a day as well as mild strength training at least three times a week. The program was personalized based on age and fitness level. The third major element was stress management, which included meditation, gentle yoga, stretching, relaxation, and breathing exercises for a total of one hour per day.

The supplement stack included omega-3, curcumin, a multivitamin, coenzyme Q10, vitamin C, vitamin B12, magnesium, probiotics, and lion’s mane mushroom.

The researchers say that while using many interventions simultaneously makes it impossible to detect each one’s effect, it is also becoming increasingly clear that such multimodal programs may have a cumulative effect and hence should be tested.

Improvements for many study group participants

The researchers report significant correlations between the degree of lifestyle change (from baseline to 20 weeks) and the degree of change in three of four measures of cognition and function. The ratio of the two types of amyloid-β peptides (Aβ42 and Aβ40), an important Alzheimer’s metric, also showed a statistically significant response to the intervention. While it increased by 6.4% in the intervention group, it declined by 8.3% in the control group. Two more biomarkers were robustly improved: the concentration of harmful LDL cholesterol and microbiome composition.

Of the 24 patients in the study group, 10 showed improvement as measured by the cognitive test CGIC. In another 7, the symptoms were unchanged, and in 7 patients, they worsened. Not a single patient in the control group improved: 8 were unchanged, and 17 worsened. These results are impressive compared to our current best anti-AD drugs, but the duration of the study was relatively short, and it is possible that the gains would have maxed out over a longer term.

Literature

[1] Ornish, D., Madison, C., Kivipelto, M., Kemp, C., McCulloch, C. E., Galasko, D., … & Arnold, S. E. (2024). Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer’s disease: a randomized, controlled clinical trial. Alzheimer’s Research & Therapy, 16(1), 122.

[2] Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., … & Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet, 396(10248), 413-446.

[3] Ornish, D., Scherwitz, L. W., Billings, J. H., Gould, K. L., Merritt, T. A., Sparler, S., … & Brand, R. J. (1998). Intensive lifestyle changes for reversal of coronary heart disease. Jama, 280(23), 2001-2007.