Mois : mai 2024

A new study suggests that aerobic medium-to-vigorous physical activity benefits obese and diabetic people the most when conducted in the evening hours [1].

Do you really need morning runs?

Physical activity is an essential part of the longevity-conscious lifestyle and one of the best life-extending interventions currently available. However, questions remain as to what types of physical activity are the healthiest, in what quantities, and so on. Exercise is a heterogeneous universe, and finding an individual mix involves such factors as age, sex, and medical conditions.

Recently, the timing of physical activity has become a widely explored issue. There is still a widespread public misconception that to lead a healthy lifestyle means to get up at six in the morning and go for a run. Many people find this regimen too hard to maintain. Thankfully, the reality seems to be more lenient. Numerous studies have suggested that at least some types of exercise bring greater health benefits when performed in the afternoon and evening hours [2].

30,000 accelerometer-wearing participants

In this new study, Australian scientists utilized data from UK Biobank, a huge repository of longitudinal health data on about half a million British citizens. A subset of UKB participants wore sophisticated accelerometers for a week to register their physical activity patterns. The resulting data has spawned numerous enlightening studies.

These researchers wanted to determine the best timing of aerobic medium-to-vigorous physical activity (MVPI) in obese and diabetic people. They assessed such outcomes as mortality, cardiovascular disease, and microvascular disease.

While the researchers used their own sophisticated way to categorize physical activity, generally, medium physical activit is between 3 to 6 metabolic equivalents (METs), a scale in which 1 is energy consumption at rest and vigorous is everything north of 6. For instance, brisk walking falls into the medium category, while jogging is considered vigorous.

Aerobic MVPI was defined in this study as at least three continuous minutes of MVPI. The participants were divided into three groups according to when in the day most of their MVPI occurred: 6 AM to 12 PM for the morning group, 12 AM to 6 PM for the afternoon group, and 6 PM to 12 AM for the evening group.

Of about 30 thousand participants, all with body mass indices (BMIs) of more than 30, 2,995 had type 2 diabetes at baseline. The median age was 62, and gender distribution was fairly even. All results were controlled for potentially confounding factors, including non-health-related deaths, cholesterol levels, blood pressure, ethnicity, socioeconomic status, and the season of accelerometer wear time.

Go for a walk after work

The reference group included people who averaged less than one bout of aerobic MVPI per day. Compared to that group, all those who were more active showed less all-cause mortality. However, the evening exercisers stood out with a hazard ratio of 0.39: that is, they were almost three times less likely to die than non-exercisers. The reduction in mortality was less pronounced in the morning and afternoon groups (HRs of 0.67 and 0.60, respectively).

People diagnosed with type 2 diabetes seemed to benefit from evening exercise even more (HR of 0.24, which translates to more than a four-fold reduction in all-cause mortality). Afternoon MVPI also showed strong results in this subgroup (HR of 0.44). Interestingly, no statistically significant association was found for morning exercisers in this subgroup (HR of 0.86).

The results were largely similar for cardiovascular disease, with modest and almost similar reductions for the morning and afternoon groups (HR of 0.83 and 0.84 respectively), and a much larger one for the evening group (HR of 0.64). In the subset of diabetic participants, only evening exercise showed a statistically significant effect: HR of 0.54.

Different results were recorded for microvascular disease, which included nephropathy, neuropathy, and retinopathy. Here, all groups showed rather small effect sizes, although evening exercise still came out on top.

The frequency of aerobic bouts seemed to be more important for their association with health outcomes than the overall duration of daily activity. Concordantly, recent research suggests that short bouts of physical activity can have a strong health-promoting effect [3].

Populational studies like this one can only establish correlation and not causation, and their results can be affected by hard-to-eliminate confounding factors and arbitrary design decisions.

Building upon previous clinical studies, our analyses underscore the consistent association of evening MVPA with the lowest risk in mortality, as well as strong associations with the incidence of CVD and MVD, when compared with not undertaking aerobic MVPA bouts. These findings are robust and extend to the subset of participants with T2D, in whom evening MVPA exhibited even more pronounced associations with mortality and cardiovascular morbidity. Sensitivity analyses demonstrated that when controlling for more even temporal distributions of aerobic MVPA, evening MVPA was associated with the greatest reduction in mortality, whereas more evenly spread MVPA was associated with the greatest reduction in MVD incidence.

Literature

[1] Sabag, A., Ahmadi, M. N., Francois, M. E., Postnova, S., Cistulli, P. A., Fontana, L., & Stamatakis, E. (2024). Timing of Moderate to Vigorous Physical Activity, Mortality, Cardiovascular Disease, and Microvascular Disease in Adults With Obesity. Diabetes care, 47(5), 890-897.

[2] Moholdt, T., Parr, E. B., Devlin, B. L., Debik, J., Giskeødegård, G., & Hawley, J. A. (2021). The effect of morning vs evening exercise training on glycaemic control and serum metabolites in overweight/obese men: a randomised trial. Diabetologia, 64(9), 2061-2076.

[3] Stamatakis, E., Ahmadi, M. N., Gill, J. M., Thøgersen-Ntoumani, C., Gibala, M. J., Doherty, A., & Hamer, M. (2022). Association of wearable device-measured vigorous intermittent lifestyle physical activity with mortality. Nature Medicine, 1-9.

Researchers have discovered negative ways in which intestinal bacteria change over time, spurring gut inflammation, and introduced older bacteria into a population of younger mice to determine their effects.

A well-known link

It has been thoroughly documented that gut bacteria have an influence on aging [1], and age-related changes to gut inflammation can lead to systemic inflammation [2, 3]. This has been proposed as a cause of inflammaging, the age-related increase in inflammation that leads to a host of order disorders.

These researchers attempted to shed more light on this subject by directly analyzing the guts of younger and older mice and then determining what effects that their respective bacterial populations were having.

Some bacteria are better than others

First, the researchers compared the colonic contents of 3- to 4-month-old and 19- to 20-month-old Black 6 mice, comparing diversity and taxonomic diversity. Their findings concurred with those of previous work involving human beings, showing that such taxonomic groups as Bacteroides were more common in the young than the aged, being replaced by such groups as Clostridium. Also as in previous work, gut diversity significantly decreased with age.

Inflammatory compounds were also more strongly expressed in the colons of older mice, including chemokine ligand 2 (Ccl2), which attracts macrophages. Calprotectin, which is found in immune cells and is a marker of inflammatory bowel disease (IBD) in people, was far more prevalent in the guts of the old mice. These changes in gene expression revealed that bacteria had become embedded into the tissues of the gut and that immune cells were present to fight them.

Specific bacterial changes were associated with these inflammatory markers. In particular, an increase of Erysipelatoclostridium and a decrease of Lachnospiraceae were found to be associated with more calprotectin and an increase in inflammatory signaling.

The researchers focused on one particular inflammatory signal, toll-like receptor 4 (TLR4). They found that bacterial samples taken from aged mice had more effect than those of young mice in activating TLR4 in immune cells, regardless of what area of the gut the samples were taken from. A related compound, TLR5, was found to be statistically unaffected.

Aged bacteria cause some inflammation in young animals

In another experiment, these researchers transplanted bacteria from the guts of old or young mice into those of young mice that had been raised without any gut bacteria at all. Four weeks later, the young mice whose intestines were colonized by bacteria from younger mice fared much better than those that had received bacteria from older mice. The aged-bacteria recipients had considerably greater inflammation in the colon and more signs of toxicity.

However, these younger animals were able to negate some of the effects. TLR4 was not found to be elevated after four weeks, and Erysipelatoclostridium levels did not differ between the recipients at that time point either. This demonstrates that the intestines of the mice themselves play a role in regulating bacterial contents.

Young and old mice respond differently to antibiotics

To test the resilience of bacterial populations, the researchers gave young and old animals broad-spectrum antibiotics in their drinking water for a week. The responses of young and old animals were slightly different: for example, aged mice had their bacterial diversity further decreased, while young animals had an increase in Erysipelatoclostridium. Both age groups had decreases in Lachnospiraceae, which produce the vital compound butyrate and are associated with less inflammation. Antibiotic treatment, like aging, was also found to cause an increase in reactive oxygen species (ROS).

These findings highlight the potential dangers of broad-spectrum antibiotic use while opening up questions relating to the relationship between bacteria and aging. It is largely explained how harmful bacteria that accumulate with aging can cause colonic inflammation; however, it is still unexplained exactly how younger animals maintain relatively healthier gut populations even after being exposed to aged bacteria.

Literature

[1] DeJong, E. N., Surette, M. G., & Bowdish, D. M. (2020). The gut microbiota and unhealthy aging: disentangling cause from consequence. Cell Host & Microbe, 28(2), 180-189.

[2] Malik, J. A., Zafar, M. A., Lamba, T., Nanda, S., Khan, M. A., & Agrewala, J. N. (2023). The impact of aging-induced gut microbiome dysbiosis on dendritic cells and lung diseases. Gut Microbes, 15(2), 2290643.

[3] Thevaranjan, N., Puchta, A., Schulz, C., Naidoo, A., Szamosi, J. C., Verschoor, C. P., … & Bowdish, D. M. (2017). Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell host & microbe, 21(4), 455-466.

Scientists have successfully used heart muscle cells created from induced pluripotent stem cells to counter the deleterious effects of heart attack in non-human primates.

Reprogrammed cells for heart regeneration

Since Dr. Yamanaka’s discovery, there has been a massive effort to turn this discovery into working therapies, with some of those experimental treatments currently nearing fruition. For instances, induced pluripotent stem cells (iPSCs) can be differentiated again into various types of youthful functioning cells.

Scientists have tried for a while to utilize iPSC-derived heart muscle cells (cardiomyocytes), to treat the consequences of myocardial infarction (heart attack) [1]. Healing after a heart attack is imperfect: stiff fibrotic scar tissue forms where healthy muscle was, leading to impaired heart function. However, attempts to infuse the healing muscle with iPSC-derived cardiomyocytes have been hampered by poor engraftment and posttransplant arrythmias, the latter caused by significant differences between the electrical qualities of adult cardiomyocytes and iPSC-derived ones.

Furthermore, before such problems can arise, most injected cardiomyocytes are thought to be simply washed away by circulating blood. Even those that remain are subject to a special type of cellular death, anoikis, caused by poor attachment to the extracellular matrix.

Spheroids instead of single cells

The Japanese researchers who authored this new study had learned about all these problems the hard way, from the results of their previous studies. This time, they decided to do things differently. In this new study performed on non-human primates (cynomolgus monkeys), which are far better models than rodents, instead of inoculating the monkeys with “free-floating” iPSC-derived cardiomyocytes, the researchers used spheroids: tiny balls of cells that form after several divisions. The researchers hoped that this would lead to better survival, engraftment, and integration of the cells into the existing electrical network of the heart muscle.

After receiving frozen human iPSCs from Kyoto University, the researchers differentiated them into cardiomyocytes. The cells were then frozen again for transportation to the animal lab and thawed without hurting their viability. The freezing-thawing part, according to the authors, is important because it shows suitability for future clinical use. Having grown the spheroids, the scientists injected them into 10 monkeys who had undergone heart attacks.

Partial rescue of heart damage

At first, the dose used was 20 million cells. Four weeks after transplantation, the heart contractile function of the treated monkeys was significantly improved versus controls, but the difference fell below the level of statistical significance at the 12-week mark, despite the difference between the 4-week and the 12-week readings being minuscule.

Since the resulting grafts were small, the researchers decided to increase the dose. Another ten monkeys were inoculated with 60 million cells each. This led to much better engraftment and to sustained (albeit only slightly bigger) benefits in cardiac function. Moreover, the improvement at the 12-week mark was more significant than at the 4-week mark. On the other hand, comparing cardiac function of the treated monkeys to that of healthy ones suggested that the treatment had only resulted in partial restoration.

Despite the greater number of transplanted cells, none of them were detected in other tissues such as lungs, suggesting highly targeted engraftment. The graft cells’ maturation levels were close to those of the host cells, and the graft was adequately supplied by blood vessels. Unfortunately, the larger dose also caused more arrythmias, but those symptoms were mild and short-lived. The researchers did not detect “any apparent immune response”, which is an encouraging result even though the monkeys were immunosuppressed.

According to the researchers, cardiac spheroids “have several advantages and may be an ideal form of a cardiomyocyte product for cardiac regenerative therapy”. For instance, they proved to be more viable than single cells, surviving for at least four hours at 4°C (39°F), which significantly improves transportability.

Literature

[1] Wu, P., Deng, G., Sai, X., Guo, H., Huang, H., & Zhu, P. (2021). Maturation strategies and limitations of induced pluripotent stem cell-derived cardiomyocytes. Bioscience Reports, 41(6), BSR20200833.