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Exploring How Caloric Restriction Impacts Telomere Length

A recent study from Penn State University may shed more light on the link between telomeres, aging, and why caloric restriction appears to influence them.

Telomeres are linked to aging

Telomeres are small protective caps on the ends of our chromosomes that guard our DNA. Telomere attrition, in which these caps slowly erode, is a hallmark of aging. The shortening of telomeres limits the amount of cell divisions, ultimately causing a decline in cell numbers in organs and tissues.

Shortened telomeres are linked to multiple age-related diseases and idiopathic pulmonary fibrosis. For that reason, telomeres, and their length and rate of loss, have long been a biomarker of aging.

They are also a potential target for therapies that restore lost telomere length, and a few companies are working on this approach. If successful, it may be possible to reduce the risks of several age-related diseases associated with short telomeres.

Investigating how caloric restriction impacts telomeres

Today, we want to highlight further data coming from the CALERIE clinical trial that could help us understand why caloric restriction may increase lifespan [1].

Last year, we wrote about how caloric restriction may slow down human aging with results from the CALERIE clinical trial. Those results suggested that caloric restriction does have a beneficial effect on longevity. However, the study also raised a number of questions and had limitations that we discussed in that article.

This time, the scientists examined the telomere lengths of 175 individuals involved in the CALERIE study. Measurements were taken at the beginning, one year in, and at the end of the 24-month study period, during which two-thirds of participants followed a caloric restriction regimen and one-third served as a control group.

The researchers noted that during the course of the study, the rate of telomere loss changed. In the first year, the participants on caloric restriction lost weight and saw increased telomere loss. The following year saw weight loss stabilized for those on caloric restriction. In the second year, however, the researchers found that telomere loss slowed down compared to the control group.

After the two year mark, both the test and control groups’ rate of loss was similar. There was no statistical difference between the two groups at this point.

The results are unclear

The researchers had originally hypothesized that there would be a reduction in telomere loss in the calorically restricted group; however, this was not the case. In fact, the rate of telomere attrition did the opposite and increased in the first year before stabilizing.

This study raises more questions than it answers. What would happen if the data for a third year was checked; would the telomere loss rate change again? Would that data change again in a fourth year of caloric restriction? Finally, why did the rate of loss initially speed up when the expectation was for it to slow down?

This is another demonstration that the dynamics of telomere loss are complex and not well understood. The study participants are due for another check-in at the 10-year mark, so it will be quite a while yet before we will know more.

That said, some data suggests that caloric restriction may help reduce cholesterol and blood pressure levels, so it could still be worthwhile to do it. If you want to find out more, check out our topic on fasting and time-restricted feeding.

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Literature

[1] Hastings, W. J., Ye, Q., Wolf, S. E., Ryan, C. P., Das, S. K., Huffman, K. M., … & Shalev, I. (2024). Effect of long‐term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis. Aging cell, e14149.

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LongX Launches the Xplore Program for Students

LongX, an initiative dedicated to providing early-career avenues into longevity, announced a call for applications for its 2024 Xplore Program. The program lasts from June 2024 until September 2024 and features a one-month longevity primer course followed by the opportunity to gain educational experience with a company operating in the longevity biotechnology sector.

The program is fully remote and open to high school and undergraduate students of any background. Fellows in the program will have the opportunity to learn about aging biology, product management, longevity tools and roadmaps, the ethics of aging interventions, and more. They will be guided throughout the program by university graduates and gain additional insights through fireside chats with experts.

2024 industry partners include Vincere Bio, Senexell, AgeRate, and several more.

To apply or learn more about the program, please visit LongX.

About LongX

LongX was launched in 2023 as a platform for youth interested in longevity. We prioritize fostering innovation and interdisciplinary collaboration, aiming for both short-term impact and long-term progress. We encourage exploration beyond traditional roles and aim to equip future experts with the skills to drive progress. Our Substack provides regular articles on our thoughts, experiences, and interviews.

Contact

Denisa Lepădatu, Co-Founder | Outreach

longevityxplorer@gmail.com

To do this, we need your support. Your charitable contribution tranforms into rejuvenation research, news, shows, and more. Will you help?
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A New Potential Path to Treating Kidney Fibrosis

Researchers have found a new protein target for senescence-related kidney diseases and published their findings in Aging Cell.

Kidney disease and fatty acid use

Chronic kidney disease (CKD) is all too common in older people, as a full third of people over 70 have moderate to severe forms of it [1]. The kidneys need surprising amounts of blood to function, as they consume a fifth of the heart’s output [2]. They are also unusually good at metabolizing fat, but problems with this system can lead to kidney fibrosis and further problems [3]. This stems from malfunctions in fatty acid oxidation (FAO), and a decrease in the related enzymes stops fats from being used for energy [4] and is directly linked to kidney disease [5].

Previous work has found that protease-activating receptor 2 (PAR2), which promotes inflammation [6], hinders fat metabolism and encourages the development of fatty liver disease [7]. These researchers, therefore, decided to investigate the relationship between PAR2, fatty acid oxidation, kidney fibrosis, and cellular senescence in the kidneys.

Rodents’ kidneys act much like humans’

The researchers first investigated kidney disease in a standard breed of rats, comparing rats aged 6 and 20 months. Interestingly, the aging of the kidneys was found to be very sex-dependent in these animals: male rats had significant elevations in damage-related gene and protein expressions along with related physical changes, including fibrosis. Female rats had far fewer statistically significant differences in the kidneys between young and old.

These changes were found to be directly related to cellular senescence. The senescence markers p16, p21, and p53 dramatically increased, as did compounds related to the SASP. However, like the physical changes, these were only predominant in male rats.

The researchers continued their work from rats to mice. Feeding mice an adenine-rich diet harms their kidneys, but like with rats, the damage was found to be more significant in males. Also just like with the aged rats, markers of cellular senescence in the kidney tubes coincided with CKD and inflammation.

In both rats and mice, expression of PAR2 was found to be signiicantly associated with senescence and CKD, specifically in the kidney tube cells analyzed previously. In aged male rat kidneys, these were found to physically coincide in the same region. Further confirming these findings, the researchers induced kidney disease in mice by using cisplatin, finding a similar relationship between PAR2, senescence, and kidney fibrosis.

An examination at the cellular level gave some clues as to why this is the case. As expected, PAR2 was found to decrease the ability of the kidney tube cells to properly process fats. This led to accumulation of these fats and an increase in lactate brought on by glycolysis, an alternate method of energy production. There was also a reduced expression of Cpt1a, a protein that decreases with senescence.

Does taking away PAR2 fix the problem?

The researchers then performed their final steps of the experiment by acquiring a mouse model that does not express PAR2. Against adenine and cisplatin both, these PAR2-knockout mice were more resistant to induced kidney disorders, showing less senescence and less lipid accumulation in the tube cells. Inflammation and fibrosis were also decreased.

While this research showed only benefits for knocking out PAR2, it is rare that an aspect of biology can be simply taken away without side effects. Furthermore, it was not tested in naturally aged animals. Further research will need to be done to determine if anti-PAR2 therapies could potentially be used in people.

Literature

[1] Kovesdy, C. P. (2022). Epidemiology of chronic kidney disease: an update 2022. Kidney international supplements, 12(1), 7-11.

[2] Duann, P., & Lin, P. H. (2017). Mitochondria damage and kidney disease. Mitochondrial Dynamics in Cardiovascular Medicine, 529-551.

[3] Kang, H. M., Ahn, S. H., Choi, P., Ko, Y. A., Han, S. H., Chinga, F., … & Susztak, K. (2015). Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nature medicine, 21(1), 37-46.

[4] Miguel, V., Tituaña, J., Herrero, J. I., Herrero, L., Serra, D., Cuevas, P., … & Lamas, S. (2021). Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis. The Journal of clinical investigation, 131(5).

[5] Kang, H. M., Ahn, S. H., Choi, P., Ko, Y. A., Han, S. H., Chinga, F., … & Susztak, K. (2015). Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nature medicine, 21(1), 37-46.

[6] Heuberger, D. M., & Schuepbach, R. A. (2019). Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thrombosis journal, 17(1), 4.

[7] Rana, R., Shearer, A. M., Fletcher, E. K., Nguyen, N., Guha, S., Cox, D. H., … & Kuliopulos, A. (2019). PAR2 controls cholesterol homeostasis and lipid metabolism in nonalcoholic fatty liver disease. Molecular Metabolism, 29, 99-113.