Mois : juin 2024

Publishing in The Lancet, scientists have shown that simple walking can have significant effects on the recurrence of back pain and disability metrics.

Age-related and more than just annoying

While not as lethal as heart attacks and cancer, low back pain is also an age-related disease. According to WHO, “in 2020, low back pain affected 619 million people globally and it is estimated that the number of cases will increase to 843 million cases by 2050, driven largely by population expansion and ageing”.

Low back pain limits mobility, decreases quality of life, and thus contributes to further age-related deterioration [1]. Once a person first experiences low back pain, the risk of recurrence is very high [2]. Treatment includes invasive procedures such as surgery and rehabilitation via physical activity. Some types of exercise have shown good results in clinical trials, but many of them require specialized equipment and close supervision [3].

Walking away from pain

What about something as simple as walking? Here, opinions among scientists and the general public differ. In this paper, scientists have reported on the first randomized controlled trial to investigate the efficacy of walking in preventing the recurrence of low back pain.

The scientists recruited 701 patients who had recovered from an episode of non-specific low back pain within the previous six months. The intervention itself was delivered by private physiotherapy clinics across Australia. The guideline was to walk five times per week for at least half an hour a day, but the physiotherapists were authorized to individualize the program to increase adherence.

The consulting physiotherapists also educated their patients from the treatment group on basic strategies on how to mitigate the risk of recurrence and how to deal with mild recurrence episodes. There were other limitations to the study as well: for instance, participants in the control group were not barred from seeking other care for their condition, and the prevalence of women was high (81%). All of this might have affected the results.

The participants’ median age was 54. Most of them already had several recurring episodes of low back pain (median 33 episodes) and had reported a high perceived risk of recurrence. The chosen primary outcome was the number of days between randomization and the first recurrence of activity-limiting low back pain.

Significant risk reduction

In the study, walking reduced the risk of an activity-limiting recurrence by 28%. The median number of days between recurrences was almost twice as high in the intervention group as in the control group (208 days and 112 days respectively). These differences were highly statistically significant.

For the incidence of episodes that caused participants to seek care, the difference was even bigger, with a 43% risk reduction.

Interestingly, over the course of the study, members of the control group also significantly increased their walking activity, although not as rapidly as the study group. At baseline, the reported number of minutes of walking per week was 70 for the study group and 67 for the control group. At the three-month mark, it was 165 and 114 minutes, respectively, and a year after the beginning of the study, 160 and 159. This is a well-known effect in which the control group, conscious of not receiving the intervention, begins mimicking it voluntarily. The control group was also much more likely to seek additional care, such as massage and physiotherapy.

Despite the control group eventually catching up with the study group in walking, significant differences in disability score remained until the end of the study and even increased. While patients in the study group reported a marked decline in disability score, it was much more attenuated in the control group. Statistically significant differences in perceived quality of life, favoring the control group, were detected at most timepoints.

An individualized, progressive walking and education intervention substantially reduced low back pain recurrence compared with a no treatment control group in adults who were not previously engaging in regular physical activity. This finding was consistent across the primary and two secondary recurrence outcomes. There were also reductions in back pain-related disability in the intervention group for up to 12 months, and the intervention had a high probability of being cost-effective from the societal perspective compared with a no treatment control.

Literature

[1] Gore, M., Sadosky, A., Stacey, B. R., Tai, K. S., & Leslie, D. (2012). The burden of chronic low back pain: clinical comorbidities, treatment patterns, and health care costs in usual care settings. Spine, 37(11), E668-E677.

[2] da Silva, T., Mills, K., Brown, B. T., Pocovi, N., de Campos, T., Maher, C., & Hancock, M. J. (2019). Recurrence of low back pain is common: a prospective inception cohort study. Journal of physiotherapy, 65(3), 159-165.

[3] Steffens, D., Maher, C. G., Pereira, L. S., Stevens, M. L., Oliveira, V. C., Chapple, M., … & Hancock, M. J. (2016). Prevention of low back pain: a systematic review and meta-analysis. JAMA internal medicine, 176(2), 199-208.

Researchers have discovered one of the reasons why fatty liver disease, even without alcohol consumption, increases with aging.

The earliest stage of fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) begins with steatosis, the accumulation of fatty tissues in an organ [1], which can then progress to hepatitis, fibrosis, and cancer [2]. Therefore, fat accumulation in the liver isn’t just a matter of obesity or fat accumulation in general: it is a direct precursor to liver failure. NAFLD increases with aging, and this fact has been re-confirmed in multiple studies encompassing multiple populations and time periods [3, 4, 5].

The acyl-coenzyme A (acyl-CoA) dehydrogenases are key elements of lipid metabolism and synthesis in the liver, as they form acetyl-CoA, a precursor of lipid formation [6]. Blocking the formation of acetyl-CoA promotes autophagy and lengthens lifespan in simple organisms [7]. This research focuses on the short-chain form of acyl-CoA dehydrogenase (SCAD), which these researchers believe to be key to the gradual formation of NAFLD.

SCAD is linked to both liver disease and aging

This paper began with a gene set analysis taken from younger (21-45) and older (70+) people. As expected, genes related to fatty acid metabolism were strongly upregulated in the older group. ACADS, which encodes for SCAD, was significantly upregulated among this gene set. In groups of young. middle-aged, and older mice, the genes for very long, long, and medium-chain fatty acids did not significantly change; only the gene for SCAD did.

Liver tissue analysis showed similar results, with people older than 74 producing much more of it than 18- to 25-year-olds. Peripheral blood mononuclear cells (PBMCs), which are easy to access and naturally produce SCAD, also produce much more of it in this older cohort. Inducing senescence into a human liver cell line through hydrogen peroxide also caused these cells to express more SCAD along with the senescence marker p21.

Gene expression of SCAD was positively correlated with NAFLD. People with this disease were age-matched with healthy controls, and the healthy controls had far less SCAD than the people with NAFLD. Unsurprisingly, even in the NAFLD patients, the amount of SCAD was increased with age.

Life without SCAD?

The researchers utilized a mouse strain that had the ACADS gene completely knocked out, and analysis of their liver tissues confirmed that these mice did not produce any SCAD. While their total bodyweights were the same, older mice of this strain had far less evidence of liver steatosis compared to similar mice that produced SCAD. Fibrosis was also greatly diminished in the SCAD-free mice, as were standard biomarkers of cellular senescence, and embryonic fibroblasts derived from these SCAD-free mice were more able to consume lipids after multiple replications and had less DNA damage.

Additionally, the cellular housecleaning mechanism known as autophagy was strongly downregulated with SCAD. With aging, the cells of SCAD-free mice still engaged in less autophagy than younger mice, but multiple biomarkers confirmed that their autophagy was still greater than older mice that produce SCAD. Further experiments found this to be directly related to the acetyl-CoA pathway.

While most of these results were positive, one crucially negative result was found: the mice without SCAD production produced significantly less ATP, particularly with aging. This is the crucial molecule used for mitochondrial energy production. While it may be possible to alleviate NAFLD by targeting SCAD in people, the deveopers of any future drug must take potential side effects related to energy metabolism into account.

Literature

[1] Chalasani, N., Younossi, Z., Lavine, J. E., Diehl, A. M., Brunt, E. M., Cusi, K., … & Sanyal, A. J. (2012). The diagnosis and management of non‐alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology, 55(6), 2005-2023.

[2] Wang, H., Naghavi, M., Allen, C., Barber, R. M., Bhutta, Z. A., Carter, A., … & Bell, M. L. (2016). Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. The lancet, 388(10053), 1459-1544.

[3] Miyaaki, H., Ichikawa, T., Nakao, K., Yatsuhashi, H., Furukawa, R., Ohba, K., … & Eguchi, K. (2008). Clinicopathological study of nonalcoholic fatty liver disease in Japan: the risk factors for fibrosis. Liver International, 28(4), 519-524.

[4] Kagansky, N., Levy, S., Keter, D., Rimon, E., Taiba, Z., Fridman, Z., … & Malnick, S. (2004). Non‐alcoholic fatty liver disease–a common and benign finding in octogenarian patients. Liver International, 24(6), 588-594.

[5] Hilden, M., Christoffersen, P., Juhl, E., & Dalgaard, J. B. (1977). Liver histology in a ‘normal’population—examinations of 503 consecutive fatal traffic casualties. Scandinavian journal of gastroenterology, 12(5), 593-597.

[6] Ghosh, S., Kruger, C., Wicks, S., Simon, J., Kumar, K. G., Johnson, W. D., … & Richards, B. K. (2016). Short chain acyl-CoA dehydrogenase deficiency and short-term high-fat diet perturb mitochondrial energy metabolism and transcriptional control of lipid-handling in liver. Nutrition & metabolism, 13, 1-17.

[7] Eisenberg, T., Schroeder, S., Andryushkova, A., Pendl, T., Küttner, V., Bhukel, A., … & Madeo, F. (2014). Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. Cell metabolism, 19(3), 431-444.

It has been known for many years that microgravity in space interferes with human physiology in negative ways. As early as the first Apollo missions, astronauts experienced heart rhythm issues, low blood pressure, inner ear problems, and bone loss.

Researchers at the Buck Institute have published a fascinating new study that shows the influence of microgravity on immune cells [1]. This study is a world first that demonstrates these effects on a single-cell basis.

Previous studies had shown that immune cells do not function well in microgravity, but the reason why had remained elusive. The researchers at the Buck set out to determine what mechanisms and gene pathways are responsible for this phenomenon.

Simulating space here on Earth

The researchers simulated a microgravity environment and observed its effects on immune cells. They examined a variety of immune cells including monocytes, dendritic cells, B cells, T cells and NK cells in microgravity. The cells were taken from 27 healthy donors aged from 20 to 46 years old.

The simulation lasted for a total of 25 hours using a Rotating Wall Vessel, a device created by NASA to mimic a microgravity environment. This vessel helps cells grow in a way that is similar to how they would grow in space.

It has a motor that spins the container around and a pump that brings in clean air and releases it through a rotating part of the container. This helps create a suitable environment for cells to grow in. The team used RNA sequencing and super-resolution microscopy to observe the differences between immune cells grown in this environment and a more normal one.

Alongside the simulation, they also used data taken from the Inspiration-4 (I4) mission, the JAXA (Cell-Free Epigenome) mission, a twin study, and spleens from mice on the International Space Station. This allowed them to create a detailed picture of how a microgravity environment impacts immune cell function.

The researchers identified a number of genes and pathways that were negatively affected by microgravity. These then go on to impact the function of our immune cells.

Quercetin may protect immune cells from microgravity

Once the researchers understood how the immune cells were being impacted, it was time to see if they could stop it. They began to search through libraries of drugs and supplements, looking for any that had a protective effect against microgravity.

To do this, they used a machine learning approach developed by Dr. David Furman at his lab at the Buck Institute. This system is able to analyze millions of interactions taking place between genes, drugs, and supplements.

While the research team identified a number of potentially interesting drugs and compounds, it was quercetin that interested them the most. Quercetin is a natural antioxidant found in various fruits and vegetables, and it is a popular dietary supplement believed to have anti-aging properties.

Quercetin has been a focus of interest in aging research for quite some time. It was first catapulted into the spotlight when researchers found that it has a useful senolytic effect when combined with the drug dasatinib.

According to these researchers’ data, quercetin may reverse around 70% of the negative changes caused to immune cells by microgravity. That means that it has a protective effect against excessive levels of reactive oxygen species provoked by microgravity.

Reactive oxygen species are involved in inflammation and play a significant role in aging, particularly in the context of damage to our mitochondria, the power stations of our cells. So reducing the presence of them is a good strategy if we want to keep our cells in good condition, even more important in space than it is on Earth.

This is the first study to find potential solutions to combating the effects of microgravity on our immune cells. These findings are not only relevant to the brave men and women pioneering space, they also apply to those of us here on Earth, as these researchers intend to explore the potential effects of these interventions on ordinary immune system aging. It is possible that compounds such as quercetin may find wide value against immunosenescence in the not-too-distant future.

Literature

[1] Wu, F., Du, H., Overbey, E. et al. Single-cell analysis identifies conserved features of immune dysfunction in simulated microgravity and spaceflight. Nat Commun 15, 4795 (2024). https://doi.org/10.1038/s41467-023-42013-y