Mois : juillet 2024

Researchers compared general nutritional advice to individualized nutritional advice in addition to an app that encourages its users to follow a diet. Elderly overweight and obese people benefited more from the individualized approach [1].

One size doesn’t fit all

Proper diets can help people stay healthy even into old age. However, nutrition advice is designed for the average person, and it does not consider the high variability among people’s nutritional needs and preferences. Personalized nutrition approaches address this need to optimize the diet for the individual. Such personalized nutrition can also be considered a therapeutic approach to preventing or managing chronic diseases.

However, sticking to a strict, individualized diet might be difficult for most people. The current study’s authors believe that digital tools can help support and motivate individuals to follow the recommended diet. Therefore, they created a trial that determined whether individualized dietary interventions alongside a digital tool can affect the health of overweight and obese older adults.

Usual-care vs. individualized diet

The study included 127 participants who were between the ages of 50 and 80 and had a BMI o at least 27. Participants had to have at least one risk factor, such as type 2 diabetes, hypertension, high cholesterol, or sedentary behavior. The trial lasted 12 weeks and had a 3-month follow-up.

The usual-care group followed Healthy Eating Plate (Harvard) and the Spanish Society of Community Nutrition’s dietary guidelines. These guidelines include recommendations regarding food groups, serving sizes, frequency of consumption, and practical tips for designing menus.

They also attended online sessions to learn about prescribed dietary patterns, food label use, seasonal shopping lists, meal plans and recipes, and sleep habits.

The precision diet group received guidelines to follow a Mediterranean and mixed diet that included foods based around personal preferences, such as smoothies, fruit compote, and wholemeal bread. These foods were designed specifically for this study, and their ingredients were chosen to prevent age-related diseases. Also, only the members of this group had their caloric intake needs assessed and attended visits to supervise diet adherence.

The precision diet group’s app was also specifically designed for this study with the needs of the elderly in mind, being easily accessible and easy to use. It contained information about the assigned diet, reminders about follow-up visits, and motivational messages.

At the end of the study, participants filled out a dietary intake questionnaire recalling their 7-day food intake, physical activity, and health status and took tests to assess cognitive functions.

Eating your way to better metabolic parameters

Analysis of the obtained data revealed that, after three months of diet, both groups experienced significant reductions in body weight, BMI, and diastolic blood pressure. Still, the changes in the precision diet group were significantly greater than those in the usual-care group.

There were also differences between groups. On average, the participants who followed the precision dietary intervention finished the study with reduced waist circumference, waist-to-hip ratio, fat mass, and systolic blood pressure compared to the usual-care group.

The researchers also measured biochemical parameters, with both groups showing significantly better triglyceride and uric acid concentrations that were not significantly different between the groups. Uric acid was used here as a marker of the anti-inflammatory effects of the nutritional strategies, suggesting that both dietary approaches impact the inflammatory aging environment (inflammaging). However, there is a need to assess more inflammatory biomarkers to gain a better understanding of the underlying mechanisms behind these diets.

The precision diet group also had significantly lower total cholesterol and HDL-c levels and hadd improved glycemic control and hepatic health markers, compared to both baseline and the usual-care group.

The researchers measured total energy intake but didn’t observe differences between the groups. However, the groups differed regarding specific food groups, with carbohydrates, proteins, and fiber content significantly higher and lipids lower in the precision group.

The precision group also consumed less sodium but more sugar than the usual-care group. The researchers point out that most of the sugars in the diet participants ate came from fruit, vegetables, and dairy products. While free sugars should be limited in the diet, there is no evidence regarding the adverse effects of consuming sugars that occur naturally in fruits, vegetables, or milk. The results of this study also support this, as the researchers didn’t observe any negative effects regarding glucose metabolism in precision group participants. They hypothesize that interaction with fiber and “other nutrients could positively influence the regulation of glucose homeostasis and metabolism” [2].

Better diet, better quality of life

Based on the questionnaires that the participants filled out upon completion of a 3-month study, the members of the precision diet group improved their quality of life. Specifically, the precision diet group reported improvements in the quality of life test’s vitality, body pain, and emotional role sections. Both groups reported improvements in the general health and physical function. Statistical analysis revealed many associations between improvements in well-being and the metabolic changes observed in the participants.

The authors believe that in the future, the use of big data and -omics technologies will allow for even more personalized nutritional approaches. Such a strategy holds the potential to better aid in developing nutritional approaches that will allow for avoiding diseases and reducing the effects of aging.

The researchers point to a few limitations of the study, such as baseline dietary intake not being assessed, potential biases from self-reporting, low sample size, the mobile app not being assessed alone (only in combination with the diet), and the inability to conduct a double-blind trial due to the nature of the intervention.

Literature

[1] Galarregui, C., Navas-Carretero, S., Zulet, M. A., González-Navarro, C. J., Martínez, J. A., de Cuevillas, B., … & Abete, I. (2024). Precision nutrition impact on metabolic health and quality of life in aging population after a 3-month intervention: A randomized intervention. The Journal of nutrition, health and aging, 28(7), 100289.

[2] Müller, M., Canfora, E. E., & Blaak, E. E. (2018). Gastrointestinal transit time, glucose homeostasis and metabolic health: modulation by dietary fibers. Nutrients, 10(3), 275.

A new study describes a method of genetically modifying a fraction of tumor cells, programming them to self-destruct and take therapy-resistant cells with them [1].

Resisting the resistance

Advanced solid tumors remain the main challenge for modern oncology. It’s hard to deliver a therapy to all of the cells in a tumor, and then the issue of resistance often pops up. Some cancer cells can be resistant to a specific therapy [2], and even if it wipes out most of the cells, the surviving ones multiply as fast as cancer cells can, leading to renewed tumor growth.

Resistance can be pre-existing or acquired. In the former case, due to the genetic heterogeneity of the tumor, some cancer cells within it will have developed mutations or characteristics that make them resistant to treatment even before it is applied. In the latter case, resistance develops after the initial exposure to the treatment.

Advances in science have produced mind-blowing therapies. For instance, a genetic “kill switch” can now be introduced to a cell via viral vectors [3]. However, there’s a major obstacle, especially in the dense tumor microenvironment: the rate of penetration is low. What good would it do to kill a fraction of the cells if the remaining ones will quickly reproduce to take their place?

Survive and outcompete

A new study by scientists from Pennsylvania State University offers an elegant solution to both those problems by making use of cancer’s natural evolutionary dynamics.

First, viral vectors carrying two “switches” are introduced, and they infect some of the cells in the tumor. The first switch makes those cells resistant to a therapy and provides a fitness advantage. When the therapy is applied, the sensitive cells get wiped out, leaving two major subpopulations: the cells that have acquired natural resistance and the genetically modified cells. The latter now outnumber and can potentially outcompete the former.

At some point, the second genetic switch is turned on, which triggers a “suicide with bystander effect”, killing not only the genetically modified cells but also any nearby cells. As a result, the tumor is eliminated completely with little harm to the surrounding tissue.

Source: Nature

“It not only kills the engineered cells, but it also kills the surrounding cells, namely the native resistant population,” said Justin Pritchard, associate professor of biomedical engineering and senior author on the paper. “That’s critical. That’s the population you want to get rid of so that the tumor doesn’t grow back.”

The researchers extensively tested their invention in vitro across various switches, types of cancer, types of therapies, and mechanisms of cancer resistance. It was important to optimize the switch scheduling, activating switches at exactly the right time to ensure maximum efficacy. Finally, they proved that a small population of engineered cells can take out the naturally resistant cells across a wide range of challenging scenarios. According to Pritchard, this is “one of the biggest strengths of the paper, conceptually and experimentally.”

“The beauty is that we’re able to target the cancer cells without knowing what they are, without waiting for them to grow out or resistance to develop because at that point it’s too late,” said Scott Leighow, a postdoctoral scholar in biomedical engineering and lead author of the study.

Finally, the researchers ran a survival experiment in a murine model of human non-small cell lung cancer. The mice were inoculated with a mix of cancer cells containing a small population of resistant cells and 10% genetically modified cells. This reflects well both the usual prevalence of resistant cells and the clinical rate of viral vector penetration.

All 10 mice in the control group, which lacked genetically modified cells, initially responded well to a leading anti-cancer treatment (osimertinib) but soon developed resistance. Tumor volumes then skyrocketed, and all the animals succumbed to the disease. Conversely, in the study group, all but one of the 12 mice achieved complete tumor eradication.

Their tumor volume trajectories showed how the treatment worked: after the initial response to osimertinib, the genetically modified resistant cells multiplied, leading to renewed tumor growth. Then, the second switch was turned on, killing those cells and also any naturally resistant cells that happened to be nearby.

The one mouse that didn’t make it was an outlier that had abnormal absolute tumor volume from the start. However, this case highlights the need to customize cancer therapies for each patient.

In this work, we posit that tumors can be re-engineered to be more responsive to therapeutic intervention. Our initial selection gene drive designs are feasible; they behave according to quantitative models and are robust in the face of dramatic genetic and spatial failure modes. While the gene drive approach has risks, the intractability of treatment of late-stage tumors and the dramatic genetic diversity present in tumors at baseline necessitates bold new approaches. By leveraging evolutionary models, we can design tumors that reliably and effectively target their own heterogeneity.

Literature

[1] Leighow, S. M., Reynolds, J. A., Sokirniy, I., Yao, S., Yang, Z., Inam, H., … & Pritchard, J. R. (2024). Programming tumor evolution with selection gene drives to proactively combat drug resistance. Nature Biotechnology, 1-15.

[2] Vasan, N., Baselga, J., & Hyman, D. M. (2019). A view on drug resistance in cancer. Nature, 575(7782), 299-309.

[3] Nasu, Y., Saika, T., Ebara, S., Kusaka, N., Kaku, H., Abarzua, F., … & Kumon, H. (2007). Suicide gene therapy with adenoviral delivery of HSV-tK gene for patients with local recurrence of prostate cancer after hormonal therapy. Molecular therapy, 15(4), 834-840.

Researchers publishing in Aging have found a molecule linking exercise to the inhibition of cellular senescence, one of the hallmarks of aging.

Exercise against senescence

We recently reported on a team of researchers looking to protect against chronic obstructive pulmonary disease (COPD) by focusing on possible molecular protections. These researchers have the same target, investigating aging of the lungs, but their target is quite different: this research builds upon previous work demonstrating how senescence and the SASP are connected to this and other lung diseases, such as emphysema [1], noting that fighting senescence appears to mitigate this disease in a mouse model [2].

Exercise, among its many benefits, has been found to fight against COPD [3] and reduce cellular senescence [4]; however, previous work has not discovered the molecular underpinnings of why. These researchers searched for a connection, looking for the exercise-related factor that impedes senescence.

Finding the key protein

The researchers began by cultivating mouse embryonic fibroblasts (MEFs) in either a control medium or a conditioned medium rich with the factors of C2C12 cells, a line of immortalized mouse muscle cells. The cells grown in C2C12-CM performed much better than the control group, having reduced amounts of senescence-related factors, such as SA-β-gal and p16INK4a, along with significantly more robust cellular division.

Out of 841 candidate proteins in C2C12-CM, 62 had been specifically identified as extracellular factors. Narrowing it down to proteins that had been previously found both to inhibit senescence and to be related to exercise, the researchers found only one that satisfies both criteria: pigment epithelium-derived factor (PEDF) [5, 6].

The researchers tested its effects by comparing cells that had been cultured in C2C12-CM to a group that had been cultured in that medium alongside an antibody against PEDF. The anti-PEDF group had increased amounts of key senescence factors.

Then, the researchers cultured cells in either a control medium or a medium containing recombinant PEDF. Senescence markers in the PEDF group were, as expected, significantly diminished compared to the control group. Looking into the MEFs themselves, the researchers could not recapitulate previous research showing PEDF’s effects on signaling pathways [7]; instead, they found that it reduces reactive oxygen species (ROS) in these cells.

PEDF has positive effects on mice

The researchers then turned to mice, conducting an 8-week experiment in which some mice had running wheels to use while the control group did not. The exercising mice had increased levels of PEDF throughout their bodies and fewer senescence-related factors. mRNA levels of inflammatory cytokines were also decreased in the exercising group.

The researchers then bypassed exercise entirely, injecting recombinant PEDF into mice for 4 weeks. While the effects were not as profound as in the 8-week exercise experiment, PEDF was found to decrease some senescence markers in lung tissues. In another experiment in which 6-month-old mice were subjected to a chemical that causes emphysema, the PEDF-administered group had less markers of emphysema and senescence; the lung collapses that had occurred to the control group had significantly less occurrence in the PEDF group.

PEDF’s molecular effects were found to be related to the interaction of the microRNA miR-127, which promotes senesence, and BCL-6, a protein that is negatively associated with senescence.

These results offer hope in two ways: they show a likely reason why exercise is beneficial in people with long-term lung disease, and they show the potential of PEDF as a potential drug, particularly for people who are unable to exercise. Of course, these results were in mice, and further work will need to be done to determine if direct PEDF administration is safe for humans.

Literature

[1] Tsuji, T., Aoshiba, K., & Nagai, A. (2006). Alveolar cell senescence in patients with pulmonary emphysema. American journal of respiratory and critical care medicine, 174(8), 886-893.

[2] Mikawa, R., Sato, T., Suzuki, Y., Baskoro, H., Kawaguchi, K., & Sugimoto, M. (2020). p19Arf exacerbates cigarette smoke-induced pulmonary dysfunction. Biomolecules, 10(3), 462.

[3] Amin, S., Abrazado, M., Quinn, M., Storer, T. W., Tseng, C. H., & Cooper, C. B. (2014). A controlled study of community-based exercise training in patients with moderate COPD. BMC pulmonary medicine, 14, 1-8.

[4] Chen, X. K., Yi, Z. N., Wong, G. T. C., Hasan, K. M. M., Kwan, J. S. K., Ma, A. C. H., & Chang, R. C. C. (2021). Is exercise a senolytic medicine? A systematic review. Aging cell, 20(1), e13294.

[5] Norheim, F., Raastad, T., Thiede, B., Rustan, A. C., Drevon, C. A., & Haugen, F. (2011). Proteomic identification of secreted proteins from human skeletal muscle cells and expression in response to strength training. American Journal of Physiology-Endocrinology and Metabolism, 301(5), E1013-E1021.

[6] Cao, Y., Yang, T., Gu, C., & Yi, D. (2013). Pigment epithelium‐derived factor delays cellular senescence of human mesenchymal stem cells in vitro by reducing oxidative stress. Cell biology international, 37(4), 305-313.

[7] Niyogi, S., Ghosh, M., Adak, M., & Chakrabarti, P. (2019). PEDF promotes nuclear degradation of ATGL through COP1. Biochemical and biophysical research communications, 512(4), 806-811.