Tag: Aging

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Unlocking the code of longevity: How your diet might hold the key to a sharper mind

By Divya Vimal

We’ve all grown up hearing about the virtues of eating our greens and maintaining a healthy diet. But what if I told you that beyond just keeping your body in shape, a healthy diet could be your secret weapon against the ravages of aging and even dementia in later life? Yes, that’s right- those veggies might just be your ticket to a sharper mind and a healthier future! A groundbreaking study delved into this intriguing possibility, focusing on whether a healthy diet could slow down the biological clock and reduce the risk of dementia.

The researchers examined information from the Framingham Offspring Cohort, consisting of 1,644 participants aged 60 years and older, and has been under follow-up since 1971. They used algorithms also called epigenetic clocks to measure how quickly participants were aging biologically by assessing the methylation status of the DNA in white blood cells. One such epigenetic clock is DunedinPACE, which was utilized in this study as a predictor of health-span and lifespan. Meanwhile, they assessed diet quality using the Mediterranean Dash Intervention for Neurodegenerative Delay diet (MIND) diet score and tracked the occurrence of dementia and mortality. The MIND diet has been developed for prevention of dementia, combining key principles from two healthy diets (i.e. Mediterranean diet and Dietary Approaches to Stop Hypertension Diet). The MIND diet emphasizes high intake of neuroprotective foods such as fish, green leafy vegetables, berries, and nuts, while minimizing intake of red meat, butter, sweets. The MIND diet is a composite scoring system based on components of the MIND diet. Each component of the diet was scored from zero to one, reflecting the frequency of food consumption. Scores were assessed weekly, and the total MIND diet score, ranging from 0 to 15, was calculated as the sum of the 15 component scores. Higher scores indicated better adherence to the diet over the long term. 

Excitingly, the results revealed a compelling link between diet, aging, and dementia risk. Participants who adhered more closely to the MIND diet enjoyed a slower pace of biological aging (each 1-standard deviation (SD) increase in MIND diet score associated with a 0.20-SD slower DunedinPACE). For each improvement in the MIND diet score, there was a reduction of 34 fewer incident dementia cases per 10,000 people a year, suggesting that a healthier diet could lead to fewer cases of dementia over time- a striking finding! Digging deeper, about 27% of the diet’s impact on dementia risk was attributed to its effect on the aging pace. This suggests that a good diet might protect your mind by keeping your body younger at the cellular level.

Furthermore, a slower pace of biological aging was independently associated with lower risks of both dementia and mortality. This means that not only does a healthy diet potentially safeguard your mind, but it could also help you live longer.

Covariate analysis (statistical method) including factors like socio-economic status, genetics, lifestyle, and health conditions didn’t change the main results. Interestingly, there were no significant differences in how diet affected aging based on sex or APOE4 status (a genetic risk factor for Alzheimer’s). Furthermore, the study revealed that maintaining a healthy diet at different life stages, from mid-life to older age, was associated with slower biological aging, reduced risk of dementia, and lower mortality rates. Alternatively, similar analysis with the Mediterranean Diet Score and the Dietary Guideline Adherence Index mirrored the associations between different measures of diet quality and health outcomes underscoring the well-known health benefits of the Mediterranean diet. These findings collectively underscore the significant impact of diet on aging and health outcomes, emphasizing the importance of maintaining a healthy diet throughout life.

While the study had its limitations, such as a predominantly white cohort and participant recall bias, its implications are profound. It hints at the possibility that by monitoring our biological age, we might gain valuable insights into how to prevent dementia and age-related decline. Furthermore, the study couldn’t differentiate if a healthy diet directly affected organ health, leading to slower aging (egg before the chicken) versus its impact on cellular aging indirectly preserving organ health (chicken before the egg).

In essence, this study highlights the power of diet in preserving both body and mind. It paints a hopeful picture of a future where something as simple as dietary choices could be the key to a longer, healthier life with a more agile mind. 

Original paper

Reviewed by: Aline Thomas and Trang Nguyen

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How many candles on the cake this year?

Every year as we celebrate our birthdays, we mark the addition of a year to our lives. Our birthdays determine our chronological age measured in days, months and years since the day we were born. Biological aging on the other hand is another measure of aging that accounts for the gradual accumulation of cellular and tissue damage that occurs in the body as we grow older. Aging is a natural process and various factors contribute to biological aging, including our chronological age, genetics, lifestyle, nutrition, and physical activity. Research has shown poor nutrition and low physical activity can accelerate biological aging. Accelerated biological aging is marked by increased levels of certain hallmarks of cellular damage, leading to chronic diseases. Poor nutritional habits and sedentary lifestyles have been associated with increased risk of heart diseases, high blood pressure, cholesterol and type 2 diabetes. Additionally, over 60% of the aging population (>65 years) is expected to be affected by more than one chronic disease by 2030. Research has also shown that lifestyle interventions may reduce or delay the progress of biological aging. In this regard, Aline Thomas and colleagues obtained real life data from a large cohort of US adults to study the association between lifestyle behaviors and biological aging using mathematical models. They assessed signs of aging in individuals who engaged in some form of moderate to vigorous physical activity in their leisure time and followed a diet that resembled a mediterranean diet compared to individuals who followed a less-healthy lifestyle. A Mediterranean diet focuses on plant-based foods and healthy fats. It includes vegetables, fruits, whole grains, fish and extra virgin olive oil as a source of healthy fats. The researchers studied diet, exercise, and variations in healthy lifestyle behaviors across different age groups, genders, and body mass indices (BMI).

Dr. Thomas and colleagues combined data collected over a period of 20 years from 1999-2018 for their study. The study included 42,625 participants between the ages of 20-85 and assessed the adherence to the Mediterranean diet and an exercise regimen using a point based system. Inclusion of fruits and vegetables, legumes, cereals, fish and a ratio of mono-unsaturated to saturated fats were each awarded one point. A healthy Mediterranean diet also includes a mild-moderate amount of alcohol, which is 0-1 glass for women and 0-2 glasses for men. So, a point was given if a mild-moderate amount of alcohol was consumed. Dairy products and meat are not part of the Mediterranean diet. If participants had consumed these foods but had consumed it less than a specific amount, they were still awarded a point. The points were totaled and found to be between 0 and 9. Higher scores meant a higher adherence to the Mediterranean diet. Leisure time physical activity (LTPA) describes any physical activity performed during participants free disposable time. The researchers assessed LTPA based on the frequency, duration and intensity to calculate points / scores for each activity. They categorized the activity levels based on the scores per week into four groups ranging from – sedentary (0 points), low (<500 points), moderate (500-1000 points) and high (>1000 points). Biological age was calculated using an algorithm called PhenoAge. The algorithm calculates biological age based on chronological age and 8 biomarkers obtained from blood samples.

The study included individuals across different races, socio-economic backgrounds, marital statuses, income to poverty ratios, and with various lifestyle-related factors (e.g., smoking, BMI category, total energy intake), making it a representative population of US adults. The researchers found very interesting observations relating to diet and exercise. They discovered that adherence to a relatively healthy diet and engagement in  physical activity were independently associated with a lower biological age. Participants with a healthy diet and some level of activity were on average 1 biological year younger than the participants with the least healthy diet and sedentary lifestyle. Another very interesting finding was that individuals who had a less healthy diet but who were active even at a low level showed delayed biological aging. However, delayed biological aging was not found in participants with a healthy diet and a sedentary lifestyle, suggesting that moderate physical activity is a key component of healthy biological aging.

The findings of this study reiterates the need for better lifestyle choices across all strata of the population as the results were consistent regardless of age, sex and BMI category. A nutritious diet and moderately active lifestyle can have a positive impact on health, aging and quality of life. Getting older is inevitable, but you may be one year younger with a healthy diet and an exercise routine.

Reviewed by: Trang Nguyen, Giulia Mezzadri, Erin Cullen, Maaike Schilperoort 

 

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The key to a longer life might be in skipping that midnight snack

Have you ever caved in to the temptation of a snack in the middle of the night that manifested into a quick freezer dive to grab that ice-cream or into a series of quick taps on your food delivery app to get those udon noodles? Suffice it to say that I have been a victim to this thought one too many times. Much to my chagrin, there is an abundance of evidence that suggests that eating during restricted hours of the day or time-restricted feeding (TRF) can slow down decline of bodily functions. Limiting food intake to certain hours of daytime, even if the food is not necessarily nutritious or low in calories, can prevent ageing or even kickstart anti-aging mechanisms in mice and flies with obesity or heart disease. Because ageing was dependent on when the body takes in food, these studies hint at the role of the body’s biological clock, known as circadian rhythms, in regulating health and longevity. In an unexpected new study authored by Columbia postdoc Dr. Matt Ulgherait, flies following time-restricted feeding while also balancing it with an unlimited all-access ad libitum diet, show a significant increase in lifespan. 

By structuring 24 hour day-night periods as cycles of 12 hours of light followed by 12 hours of darkness in a temperature-controlled box, the authors tested various dietary regimens for their effects on lifespan and stumbled upon one regimen that consistently showed longer lifespan along with enhanced health in the flies. This regimen cycled between a 20-hour fast starting at mid-morning (6 hours after lights on) to a 22 hour recovery period of eating ad-libitum on repeat in young flies within 10-40 day post hatching stage of adulthood. However, flies that began this regimen after reaching older age at day 40 did not show enhanced lifespan. In comparison to flies that were allowed access to food ad-libitum on a 24 hour cycle, flies following this particular fasting-feeding regimen showed a 18% increase in female lifespan and 13% increase male lifespan in their young age. Due to the cycling schedule of unlimited food access with periods of fasting, the authors termed this regimen as intermediate time-restricted feeding (iTRF).

Previous studies have shown that caloric restriction through reduced food intake, protein restriction or inhibiting insulin-like signaling can extend lifespan. However, iTRF did not appear to limit flies from eating less and in many cases, resulted in flies eating more during times of food access compared to those in the ad libitum group. Thus, lifespan extension under iTRF did not occur because of limitation in nutrient uptake. Interestingly, an iTRF regimen performed under additional treatments of either dietary protein restriction or inhibited insulin-like signaling, resulted in a marked boost in lifespan compared to iTRF alone. It therefore seems that  independent mechanisms that  can enhance lifespan can be combined to increase lifespan even more. 

While these methods provide ways to extend lifespan through incremental means, some might argue that it would be meaningless to simply survive without long-lasting health benefits. To examine whether the longer-lived flies continued to exhibit youth, scientists measured the fitness of the flies using two well-known age-related tests: the flies’ ability to climb up the plastic vial they are in and how much they accumulate in their tissues aggregates of aging proteins – polyubiquitin and p62. When compared to the ad libitum group, iTRF flies climbed much faster and had fewer polyubiquitin and p62 aggregates in the flight muscles, even after they reached an age beyond 40 days of hatching. While the gut microbiome was shown to dictate proclivity for disease and thus have an effect on lifespan, the gut tissue in iTRF flies remained healthier with more normal cells, even when the gut microbiome was depleted with antibiotics. Therefore, the flies appeared to be in optimal health conditions with fewer aging markers in addition to longer survival, demonstrating yet again that aging slowed down due to better functioning of organs.

The dietary regimen under iTRF only controls the timing of feeding but not the nutritional intake, which provided clues to the authors that perhaps the body’s natural biological clock had something to do with iTRF-mediated lifespan. The biological clock in flies consists of proteins that are also present in other organisms all the way from fungi to humans. The main molecular parts of the core circadian clock include the proteins ‘Clock’ (Clk) and ‘Cycle’ (Cyc) which activate the genes period (per) and timeless (tim), which in turn inhibit Clk and Cyc. This process is called a feedback loop which takes all of 24 hours to complete in both flies and humans, and this is how our bodies respond to light-dark cycles. Flies undergoing iTRF showed enhanced expression of Clk in the daytime and of per and tim at night time. The authors then explored the feeding behavior and metabolism of circadian clock genetic mutants undergoing iTRF and found that neither the 20 hour long fasting period nor dietary restriction in their food altered their feeding behavior when compared to normal flies under iTRF. Yet, the extended lifespan was completely missing in Clk, per and tim mutants undergoing iTRF. Even the improved health seen with an iTRF regimen through better climbing ability and less aging-protein aggregation was abolished in per mutants compared to normal flies. Shifting the iTRF cycle by 12 hours with a fasting period during the daytime abolished the occurrence of an extended lifespan. In the altered regimen, while the same cycle was now only shifted by half a day, eating at night time while fasting during the day just did not work. This discovery showed that there could be a deep link between the body’s biological timer and when during the day food is eaten that determines both longevity and well-being. 

Because shifting the fasting period to daytime did not show any benefits, the authors checked whether genes that activate during fasting are also linked to the biological clock. In fact, Dr. Ulgherait and group had already shown that disrupting tim and per genes in the gut, which is where food is processed, caused an increase in lifespan. But, iTRF included periods of starvation that could trigger different metabolic processes. Starvation induces cellular mechanisms to degrade and recycle its molecules in a process called autophagy. Interestingly, genes encoding two autophagy proteins, Atg1 and Atg8a, which are also present in humans, showed peak levels in the night time with enhanced peaks in flies under iTRF. During autophagy, there is an increased activity of cell organelles called lysosomes that contain digestive enzymes needed to break down cellular parts. The authors found that normal flies fasting under iTRF showed higher Atg1 and Atg8a expression along with more lysosomal activity but period mutants failed to do so. Using some more genetic tricks, the authors found that manipulating the level of autophagy to go up or down directly showed an effect on iTRF-mediated lifespan.

Finally, to explore the link between iTRF-mediated lifespan and autophagy, the authors used genetic tools to increase night-specific levels of Atg1 and Atg8a. In a surprising revelation, flies with night-specific expression of Atg1 and Atg8a showed an increase in lifespan, even when these flies did not undergo fasting and were fed ad libitum. Subjecting these genetically altered flies to iTRF did not additionally increase their lifespan, suggesting to the authors that circadian enhancement of cellular degradation under an all-access diet provides the same beneficial effects as fasting done under the stricter regimen of iTRF. Flies with night-specific enhanced autophagy also showed better neuromuscular and gut health on an all-access diet. Therefore, clock-dependent enhancement of the biological recycling machinery can mimic the lifespan extension mediated by iTRF.

 

Now of course large genetic manipulations are not yet a consideration in humans but this study provides a potentially powerful yet simple change in dietary strategy that could just somehow slow down aging. Aging increases risk of mortality and disease but imagine a food intake regimen translatable from this study into humans that can help improve overall neuromuscular and gut health. So, while technology has indeed made it so much easier than before to have food at our doorstep in a few phone taps in the middle of the night, perhaps restricting the hours of when we eat can really help us live healthier lives. This study now makes me reconsider the famous quote by Woody Allen in the context of food, “You can live to be a hundred if you give up all the things that make you want to live to be a hundred”.

Dr. Matt Ulgherait is a postdoctoral researcher in the lab of Dr. Mimi Shirasu-Hiza in the department of Genetics & Development at Columbia University. Dr. Ulgherait and his colleagues also recently showed that removing the expression of the period gene from the gut tissue was sufficient to cause an increase in lifespan.

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Having the Guts to Live Forever

For most people, the famous words “Who wants to live forever?” by the British rock band Queen seem merely hypothetical. However, scientists have been trying to identify the secret of immortality for decades. Their research has revealed an important role of the biological clock in regulating lifespan. The biological clock is a natural timing device composed of small molecular “clocks” in cells throughout the body that together dictate circadian rhythm, a term that originates from the Latin words circa (around) and dies (day). As the name implies, circadian rhythm refers to all natural processes that have a period of roughly a day, such as the sleep/wake cycle, body temperature change, and release of hormones like melatonin and cortisol. Because organisms, including humans, lose circadian rhythmicity with age, scientists thought that loss of circadian regulation contributes to aging and limits lifespan. However, recent findings by Dr. Matt Ulgherait and colleagues from the Department of Genetics and Development at Columbia University, show that the relationship between circadian rhythm and lifespan is more complex than initially thought. 

Dr. Ulgherait studied the role of genes that regulate cell-intrinsic rhythms, so called “clock genes” in aging. To this end, he used the model organism Drosophila, also known as the fruit fly. Although the evolutionary distance between fruit flies and humans is large, they show a remarkably high degree of genetic similarity: about 75% of the disease-causing genes in humans match up with the genome of Drosophila. In addition, the relatively short lifespan of fruit flies of about 50 days makes them a very practical model for aging research. Dr. Ulgherait introduced loss-of-function mutations in four different clock genes in the flies, named “cycle”, “period”, “timeless”, and “clock”, and found that only disruption of cycle and clock decreased lifespan, while disruption of timeless and period surprisingly extended lifespan by about 15-20%. 

The researchers continued by investigating the specific role of period, named for its contribution to the length of circadian cycles, to find out how this gene negatively affects lifespan. Dr. Ulgherait observed that period mutant flies not only lived longer than their genetically intact counterparts, but were also leaner despite an increased food intake. Remarkably, nutrients that were taken up by the flies were not converted into storable energy but rather used for heat production, as reflected by a higher ability of period mutant flies to recover after a cold shock of 4 °C for 1 hour. When burning of nutrients is disconnected from energy production, the metabolic machinery in the cell is considered to be “uncoupled”, a process regulated by so-called “uncoupling proteins”. Dr. Ulgherait found that the expression of uncoupling proteins was consistently high in period mutant flies. Moreover, disruption of uncoupling proteins reverted lifespan of period mutants to that of control flies, indicating that uncoupled energy metabolism and increased heat generation is important for longevity.

To determine which organ of the body is responsible for the effect of period on aging, the researchers removed the gene from different tissues one by one. This way, they found that loss of the period gene in the intestine was sufficient to increase lifespan. Intestinal expression of uncoupling proteins was required for the increased lifespan in period mutant flies, indicating that an uncoupled energy metabolism in the gut is essential for longevity. To understand the underlying mechanism through which uncoupled energy metabolism in the intestine regulates lifespan, Dr. Ulgherait examined intestinal functions that are affected by aging, including intestinal barrier function, which deteriorates with aging and makes the intestines more leaky. The scientists assessed intestinal barrier function in period mutant flies by performing the “smurf assay”. This assay, named after the children’s cartoon, measures leakage of an ingested blue dye which makes the fly resemble a smurf (see image below). Indeed, period mutant flies showed a lower percentage of “smurfs” relative to controls, indicating less intestinal leakiness. Thus, loss of the circadian period gene protects against aging-related intestinal dysfunction. 

Photograph showing a normal-colored fruit fly (bottom left) with an intact intestinal barrier function and “smurf” flies (right and top left) with a disrupted intestinal barrier function. Source: The Scientist.

In summary, the research by Dr. Ulgherait and colleagues shows that disruption of circadian rhythm affects lifespan by modulating uncoupled energy metabolism in the gut. Although this research was performed in Drosophila, genetic variability in uncoupling proteins has been shown to predict longevity in humans. Therefore, pharmacological targeting of uncoupling may be one of the keys for increasing lifespan. So perhaps we should avoid hypotheticals and actually start asking the question: “Would you want to live forever?”

 

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