Imagine a world where a simple change in diet could slow down ageing. Scientists have long studied the effects of caloric restriction on ageing, hoping to find ways to extend healthy lifespan. Recent research from the CALERIE 2 study explored whether long-term CR can impact telomere length (TL), a marker of biological ageing, in healthy adults.
What is Caloric Restriction?
Caloric restriction (CR) involves consuming fewer calories than usual while ensuring adequate nutrition. This approach aims to reduce calorie intake without causing malnutrition, ensuring the body still gets all essential nutrients. Extensive research on CR has shown remarkable results in extending lifespan and delaying the onset of age-related diseases in various animals. Studies on species ranging from yeast and worms to rodents and primates have demonstrated that CR can lead to longer, healthier lives.
Researchers believe CR works by improving metabolic health and reducing harmful processes such as oxidative stress and inflammation. Oxidative stress occurs when there's an imbalance between free radicals and antioxidants in the body, leading to cell damage. Inflammation is the body's response to injury or infection, but chronic inflammation can contribute to various diseases. By reducing calorie intake, CR lowers metabolic rates, decreases the production of free radicals, and minimizes inflammatory responses. These changes help protect cells from damage and improve overall health.
Despite these promising findings in animal studies, translating the benefits of CR to humans has proven complex. Human bodies are more intricate, and factors such as lifestyle, genetics, and environmental influences play significant roles in ageing and health. Additionally, long-term adherence to CR can be challenging for many people, raising concerns about its practicality and potential side effects. Researchers continue to investigate the best ways to harness the benefits of CR for human health, exploring various dietary strategies and their impacts on ageing and longevity.
The CALERIE 2 Study
The CALERIE 2 (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy) study is the most extensive trial to date on CR in humans. Conducted over two years, it involved 175 healthy, non-obese men and women aged 21-50. Participants were randomly assigned to either a CR group (25% reduction in calorie intake) or an ad libitum (AL) group, which continued their usual diet. The study aimed to determine if CR could slow biological ageing by measuring changes in TL.
Measuring Ageing: The Role of Telomeres
Telomeres are repetitive nucleotide sequences located at the ends of chromosomes. They act like protective caps, preventing chromosomes from deteriorating or fusing with neighboring chromosomes. Each time a cell divides, its telomeres become slightly shorter. This gradual shortening limits the number of times a cell can divide, serving as a biological clock that eventually leads to cell ageing and death.
As telomeres shorten, they trigger a DNA damage response, leading to cell cycle arrest, apoptosis (programmed cell death), or senescence (a state of permanent growth arrest). Shortened telomeres are therefore closely associated with ageing and the onset of age-related diseases such as cardiovascular disease, diabetes, and cancer. Maintaining TL is crucial for cellular health and longevity.
In the CALERIE 2 study, researchers from Pennsylvania State University aimed to investigate whether long-term CR could impact TL in healthy adults. They employed two distinct methods to measure TL:
Quantitative PCR (qPCR)
This technique measures absolute telomere length (aTL) by quantifying the amount of telomeric DNA relative to a single-copy gene. It involves amplifying telomeric DNA and comparing it to a standard curve to estimate the telomere length in kilobase pairs (kb). qPCR is a widely used method due to its accuracy and efficiency in measuring TL.
DNA Methylation Algorithm (DNAmTL)
This method estimates TL by analyzing DNA methylation patterns at specific genomic sites. Methylation is a chemical modification of DNA that can influence gene expression. Researchers have developed algorithms that use methylation data to predict TL, providing an indirect but informative measure of telomere dynamics. DNAmTL leverages large datasets and advanced statistical models to estimate TL from DNA methylation profiles.
Key Findings of the Study
The study’s results were mixed, presenting a complex picture of the effects of CR on telomere length. In the first year of the study, researchers observed trends indicating faster TL attrition in the CR group. This suggests that the initial phase of CR might accelerate ageing, as evidenced by the quicker shortening of telomeres. During this period, participants in the CR group were actively reducing their calorie intake and losing weight, which could have placed stress on their bodies and led to more rapid telomere shortening.
However, the situation changed in the second year of the study, when participants transitioned from the weight loss phase to the weight maintenance phase. During this period, TL attrition in the CR group slowed down compared to the ad libitum (AL) group, which continued their usual diet. This suggests that once participants stabilized their weight and adapted to the reduced calorie intake, the rate of telomere shortening decreased. By the end of the two-year study, there were no significant differences in TL changes between the CR and AL groups, indicating that the long-term effects of CR on TL might balance out over time.
Interestingly, the study also found that higher adherence to CR, where participants achieved closer to the prescribed 25% reduction in calorie intake, had distinct effects on TL during different phases. During the weight loss phase in the first year, those with higher adherence to CR experienced increased TL attrition, similar to the overall trend observed in the CR group. This may indicate that the metabolic stress associated with significant calorie reduction and weight loss accelerates telomere shortening initially.
In contrast, during the weight maintenance phase in the second year, higher adherence to CR was associated with reduced TL attrition. This suggests that once participants had lost weight and adjusted to their new, lower calorie intake, their telomeres stabilized and aged more slowly. This phase of adaptation may have allowed the body to benefit from the positive effects of CR, such as reduced inflammation and oxidative stress, which can protect telomeres and slow down their shortening.
Implications of the Findings
These findings highlight the complexity of CR’s effects on ageing. The initial phase of CR may induce metabolic stress, leading to faster telomere shortening. However, as the body adapts, the benefits of CR, such as reduced inflammation and oxidative stress, might become more apparent, slowing telomere attrition. This hormesis-like response suggests that short-term stress from CR could lead to long-term benefits.
The study also underscores the challenges of measuring biological ageing. Different methods of assessing TL may capture distinct aspects of ageing, and the moderate agreement between aTL and DNAmTL in the study indicates the need for multiple approaches to fully understand CR’s impact.
Study Significance
The CALERIE 2 study provides valuable insights into the effects of long-term CR on biological ageing. While the results are mixed, they suggest that CR might initially accelerate telomere shortening but later slow it down as the body adjusts. These findings open up new avenues for research, emphasizing the need for long-term studies to unravel the complex relationship between CR and ageing.
Future research should explore how different factors, such as the extent of caloric reduction and individual metabolic responses, influence the ageing process. As scientists continue to investigate, the dream of slowing down ageing through dietary interventions remains a tantalizing possibility.
Caloric restriction offers a fascinating glimpse into the potential to modulate ageing, but it’s clear that the journey from lab to lifestyle is filled with nuances. As we wait for more definitive answers, maintaining a balanced diet and healthy lifestyle remains the best approach to ageing gracefully.
The study was led by Professor Idan Shalev, at Pennsylvania State University, and is published in the journal Aging Cell.
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