Exercise Capacity and Biological Age: A Powerful Relationship

Jesse Oswald • May 29, 2024

Key Points

  • Chronological age should not be used to accurately predict morbidity and mortality since biological age is a more reliable lifespan indicator.
  • VO2 max is the gold standard method to determine exercise capacity during graded exercise testing and one of the best indicators of biological age.
  • VO2 max is the strongest independent predictor of health and longevity, and VO2 max-derived biological age allows for better risk stratification and management of individuals undertaking exercise testing.

 

Regular physical activity at both the recreational and competitive levels contributes substantially to healthy aging and health-enhancing physiological adaptations by helping to prevent or control many health problems that often reduce individuals' quality and length of life.

However, increasing age is associated with declining physical activity and changes in several physiological parameters, such as the aerobic and anaerobic energy systems.

While anaerobic power and capacity decline at similar rates at about 6-8% per decade, peak aerobic power declines much slower with age.

In keeping with the unprecedented growth rate of the world’s aging population, there is a clear need for a better understanding of the aging process and the determinants of healthy aging.

Biological Age vs. Chronological Age

Aging is a complicated process in which molecular and cellular damage accumulates, resulting in a gradual functional and structural decline, increased susceptibility to disease, and, ultimately, death. Although the prevalence of functional impairment with age is inevitable and biologically inherited, there is a tremendous individual variation in the rate and degree of physiological decline. Environmental conditions like stress, physical inactivity, and nutrition may modify these time-related deteriorations. As a result, individuals with the same chronological age vary widely in health and function. They may be younger or older than their birth date or have a different life span, the so-called biological age. This heterogeneity may be attributed to diversity in genotypes, living habits, and environments.


Consequently, when measured chronologically, age is not a reliable indicator of the rate of a physiological breakdown associated with the aging process. It should not be used to predict morbidity and mortality accurately. Therefore, to better assess an individual’s degree of aging, and thus residual life span or disease susceptibility, new approaches that provide predictive power beyond that from measuring chronological age alone need to be developed.


Biological age, which is one of them, represents the degree to which an individual has aged and may be able to provide a surrogate measure to determine an individual’s level of damage accumulation as well as the extension of a healthy lifespan. It has gained ground over chronological age since it holistically encapsulates the state of an individual’s health and accounts for some of the variations in morbidity, mortality, and other health outcomes among individuals of the same chronological age.


When measured longitudinally, biological age can be used to track the trajectory of mortality and health damage, such as myocardial infarction (ΜΙ), over time.



Studies have demonstrated that the combination of diet and exercise, in terms of both aerobic and resistance training, cannot only prevent aging but also reverse it, thereby improving biological age and increasing a healthy lifespan.

Advanced biological age, on the other hand, has been associated with disability, worse cognitive function, and mortality in older individuals.

Health Benefits of Physical Activity

While physical inactivity has been associated with greater mortality, regular aerobic exercise can slow or reverse functional deterioration, reducing an individual’s biological age by ten or more years. Regular exercise training increases a variety of physiological parameters, including elevated cardiac output, augmented blood volume, skeletal muscle angiogenesis, increased skeletal muscle mitochondrial density as well as maximal oxygen uptake (VO2 max).


VO2 max indicates the body’s ability to deliver oxygen to the working muscles, which rely on adequate oxygen supply to meet their metabolic demands.


The cardiovascular system represents the primary limitation of VO2 max, which is negatively affected by aging but can dramatically improve through exercise. 


At least 30 minutes of moderate-intensity exercise training on most days of the week can increase VO2 max by more than 20%. Although high-intensity exercise is more effective for improving VO2 max in healthy individuals, lower-intensity physical activity can also enhance VO2 max in high-risk individuals. Therefore, the level of physical activity sufficient to improve VO2 max depends on the initial fitness status and health, the training history, and the exercise's duration, frequency, and intensity.


Whereas resistance training can improve VO2 max, endurance training represents the preferred intervention to improve cardiorespiratory fitness (CRF). Endurance exercise training, especially when combined with specific respiratory muscle training, can preserve and improve VO2 max.



Besides cardiovascular fitness, exercise training can also develop and maintain strength, flexibility, bone health, coordination, and balance, all essential aspects of independent living in old age. Moreover, exercise delays the age-associated change in body composition, namely the loss of muscle mass and the increase in fat mass.

The Clinical Prognostic Value of VO2 Max

Physical fitness is typically expressed as cardiorespiratory fitness (CRF) and/or exercise capacity, and VO2 max is an objective measure. Specifically, VO2max is the gold standard for assessing the amount of oxygen consumption in a maximal effort, beyond which no increase in workload can further raise it. VO2max during exercise represents cardiac, circulatory, respiratory function, and muscle oxygen use under physiological stress conditions.


As a reasonable, direct, and objective measure of CRF, VO2max can provide a quantifiable measurement of the level of physical activity. Physical inactivity and poor physical fitness have been estimated to account for 12% of all deaths in the US. Indeed, Individuals with low VO2 max have a substantially higher risk of all-cause mortality and cardiovascular disease (CVD) compared to those with intermediate and high VO2 max.



Therefore, VO2 max is a strong predictor and independent risk factor for CVD-related and overall mortality and premature death and can be considered equally important as other conventional modifiable risk factors such as smoking, hypertension, hypercholesterolemia, obesity, and diabetes. Specifically, increased VO2 max may offset the harmful consequences of excess body fatness, hypertension, and hyperglycemia, namely major CVD risk factors, thereby allowing individuals to be ‘’fat but fit’’, meaning to have a lower risk of CVD outcomes, regardless of body mass index (BMI) levels.

Proposed Biological Age Biomarkers

During the past decades, various specific aging biomarkers have come into play in an effort to identify biological age better. They can be separated into genetic, molecular, and phenotypic biomarkers.


Genetic factors, such as telomere length, decrease progressively with aging; hence, it has been proposed as a potential marker of biological aging. Genetic factors cause approximately 20-50% of the biological variations. Recent reports have shown an association between shortened telomere length and increased risk of age-related pathologies, such as CVD and all-cause mortality. Telomeres are located at the end of human chromosomes and consist of highly repetitive DNA sequences, which shorten every time cells divide.



The results of a study demonstrated that vigorous habitual aerobic exercise and maximal aerobic exercise capacity preserve telomere length among healthy older adults. Thus, their cellular and physiologic function with aging is compared with a sedentary lifestyle or short-term exercise training. Besides telomere length, molecular indicators used as biological age biomarkers are T-cell DNA rearrangement and DNA methylation, also known as the epigenetic clock. However, the association of the above biomarkers with aging is inconsistent. Some studies show positive and other negative correlations; hence, more research is needed before they are used as established biomarkers for biological age.

VO2 Max as a Biomarker of Health and Longevity

VO2 max is a commonly used biomarker of biological age. Based on a scientific statement from the American Heart Association (AHA), it is the strongest independent predictor of future life expectancy in healthy and cardiorespiratory-diseased individuals. Age, sex, duration, intensity, frequency, type of physical activity, genetic factors, and clinical or subclinical disease determine VO2 max.

VO2 max typically decreases by about 7% (women) to 10% (men) per decade from around 25 years, and the physical activity level is directly related to the rate of this decline. For each 1ml/min/kg decrease, the risk of functional dependency increases by 14%, suggesting a need to maintain, if not improve, cardiovascular fitness.


Although genetic factors determine around 50% of VO2 max, regular endurance training can significantly improve it in 8-52 weeks by 13-20% or around 0.5L/min, depending on exercise intensity.


VO2 max, determined through cardiopulmonary exercise testing (CPET), has an inverse, graded, and independent association with all-cause mortality risk, supporting the value of exercise testing as a clinical tool; it is non-invasive, relatively inexpensive, and provides clinically relevant diagnostic and prognostic information.


Notably, among established risk factors such as hypertension, smoking, and diabetes, VO2 max achieved during a graded exercise test has the strongest inverse association with all-cause mortality and cardiac events in both a clinically referred population and among asymptomatic people of both sexes without existing cardiovascular disease.


Deriving biological age from VO2 max has great clinical utility since it may enable a more accurate risk stratification in those individuals undergoing exercise testing. For example, a trained 70-year-old can exhibit the same biological age as an untrained 50-year-old based on their VO2 max. Indeed, in a recent study, VO2 max-associated biological age demonstrated better discrimination for mortality and MI than chronological age.



Therefore, biological age may help identify those most benefit from pharmacologic and more aggressive lifestyle interventions. Furthermore, utilizing biological age provides an intuitive understanding of fitness-mediated risk and may prompt greater compliance with important lifestyle changes.

The Numbers Behind the Strong Link Between VO2 Max and Longevity

A proportionally high VO2 max is a strong clinical vital sign of health and longevity. Probably, no other biological variable has as much relevance to health and longevity as VO2 max, to an extent where a high VO2 max attenuates the negative impact of the presence of other known cardiovascular risk factors, such as hypertension, hypercholesterolemia, and diabetes.


The greatest rates of mortality are found at levels of VO2 max lower than 27.6 ml/min/kg.


Every 3.5ml/min/kg VO2 max increase corresponds to a 12% gain in life expectancy.


Furthermore, each 3.5ml/min/kg VO2 max increment in peak treadmill workload is associated with a 14% reduction in cardiac events and a 7ml/min/kg VO2 max increase in treadmill performance is related to a 30% reduction in mortality.


Among patients who have had an MI, every 3.5ml/min/kg VO2 max increase is associated with a reduction in mortality from any cause that ranges from 8-14% over 19 years of follow-up.


In a 20-year follow-up study, mortality risk was 61% lower in physically fit individuals compared with their unfit counterparts. The mortality risk was also 34% lower in participants defined as unfit during the initial exercise test, who became physically fit by the follow-up test though. Lastly, fit participants who drifted into the unfit category by the second test maintained 41% lower risk than those who were unfit in both tests.



A recent follow-up study suggested that 1ml/min/kg higher VO2 max re-examination at 11 years was associated with a 9% relative risk reduction in all-cause mortality. This study even set the threshold in the elderly at 17.5 ml/min/kg for an independent lifestyle and a higher survival rate.

Key Takeaways

Overall, fitness-related health benefits, such as the reversion of biological age, can be achieved regardless of age or fitness status. According to the AHA guidelines, the addition of VO2 max as a measure of exercise capacity for risk classification can help improve patient management and reinforce lifestyle-based strategies to improve overall health. Therefore, health professionals should encourage individuals to initiate and maintain a physically active lifestyle to improve their exercise capacity and thus lower the risk of morbidity and mortality.

An Ounce of Prevention - Hyperion Health Blog

A woman is helping an older woman do exercises on an exercise ball in a gym.

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By Jesse Oswald • January 29, 2025
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A woman is wearing an oxygen mask while running on a treadmill.

Predicting Medical Costs with VO2max

By Jesse Oswald • January 20, 2025
Highlights Healthcare expenses are skyrocketing, with consumers and employers facing the significant brunt. Identifying those likely to get sick is critical as our resource-strapped healthcare system should focus on those likely to become the most significant burden to the system. VO2 max is a crucial longevity indicator that can also accurately predict healthcare expenses. The rampant chronic disease epidemic and the resulting surge in medical expenses is one of the most dire problems of modern societies, probably only second to climate change. Healthcare inflation is on a meteoric rise, and for those with limited or no healthcare coverage, a medical emergency is the equivalent of personal bankruptcy. A dire problem for employers In the US, employers and consumers who face rising health insurance premiums and astronomical out-of-pocket medical expenses feel the brunt of rising healthcare costs. Such is the problem that even large, well-capitalized corporations choose to send employees overseas for specific medical procedures since the cost of traveling and treatment in a foreign country is lower than the cost of care in the US. Another startling example is the infamous "northern caravan," a term that describes people with diabetes in the northern states who travel to Canada to secure their insulin supply. According to McKinsey , a survey conducted among over 300 employers highlighted that the average increase in the cost of health benefits over the past three years has been within the range of 6 to 7 percent. This survey also indicated that any rate increases exceeding 4 to 5 percent were deemed unsustainable. Interestingly, 95 percent of the surveyed employers expressed willingness to contemplate reducing benefits if costs surged by 4 percent or more. The primary cost-control measures that these employers indicated they might explore included elevating the portion of premium costs covered by employees and a potential transition to high-deductible health plans. Why is Breath Analysis relevant? Vis-a-vis this problem, the early and accurate estimation of who will get sick and how much they will cost is as critical as the treatment itself. The reason is that no other method of accurately identifying at-risk populations exists; it helps focus our scarce prevention resources and attention on those most in need. Breath analysis, AKA VO2max or metabolic testing, is an assessment that reveals two key biomarkers that provide significant predictive value for one's likelihood of developing costly chronic conditions. These two biomarkers are VO2max and the Respiratory Exchange Ratio. In this article, we will dive into VO2max to understand why it's a critical reflection of our overall health and, consequently, a window into our future healthcare spend. What is VO2max? Let's start with the basics. What is VO2max? VO2 max is the maximum amount of oxygen the human body can absorb. It is measured in terms of milliliters of oxygen consumed per kilogram of body weight. The below formula below indicates how VO2max is calculated: The numerator indicates the volume of oxygen your heart, lungs, and cells can absorb, expressed in milliliters per minute. The denominator indicates the weight of the individual represented in kilograms. 
There are many different types of fats in this picture.

Dietary Fat: An Essential Dietary Component Rather than the root of all Nutritional Health Issues

By Jesse Oswald • January 13, 2025
Key points A total fat intake between 20-35% ensures sufficient intake of essential fatty acids and fat-soluble vitamins Omega-6 PUFAs are primarily found in vegetable oils, while omega-3 PUFAs are primarily found in fatty fish and fish oils Both omega-3 PUFAs and MUFAs have established benefits for cardiovascular disease TFAs are the only dietary lipids that have a strong positive relationship with cardiovascular disease Omega-3 PUFA supplementation increases the beneficial bacteria of the human microbiome Over the last three decades, there has been a great revolution against fat due to its suspected association with several nutritional health issues, especially cardiovascular disease. There was a tremendous amount of evidence that indicated dietary cholesterol and saturated fat as the main culprits of cardiovascular disease, thus morbidity and mortality. It was when all the low-fat and no-fat dairy products started to launch, promising even complete substitution of the cholesterol-lowering heart medication if these products were exclusively consumed. Let’s start from the beginning. Dietary fat intake can vary significantly and still meet energy and nutrient needs. International guidelines suggest a total fat intake between 20% and 35% of the daily caloric consumption. This range ensures sufficient intake of essential fatty acids and fat-soluble vitamins. Not only does the quantity of the ingested fat matter, but most importantly, its quality. Some dietary fats have beneficial effects, with a significant role in maintaining good health, while others may threaten it. Which are, after all, the dietary fats? Dietary fats is a rather heterogeneous group of organic compounds, including four main types of fat, which are elaborately described in the following sections of this article. Polyunsaturated fatty acids (PUFAs) Polyunsaturated fatty acids (PUFAs) have two or more carbon-carbon double bonds. Omega-6 PUFAs and omega-3 PUFAs are the main types of PUFAs and are classified according to the location of the first unsaturated bond (sixth and third carbon atom, respectively). Alpha-Linolenic acid (ALA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA) are the most important omega-3 PUFAs. ALA is an essential fatty acid that can only be obtained from diet and can be converted into EPA and then to DHA, but the rate of this conversion is finite, approximately 7.0%–21% for EPA and 0.01%–1% for DHA. In the same way, the most important omega-6 PUFAs are linoleic acid (LA) and arachidonic acid (ARA). LA is an essential fatty acid that, in order to give rise to ARA, needs to be ingested through the diet as the human body cannot synthesize it. The recommended intake for total PUFA ranges between 5% and 10% of the total energy intake, while a total omega-3 PUFA intake of 0.5%–2% and a total omega-6 PUFA intake of 2.5%-5% is suggested. A dietary ratio of omega−6/omega−3 PUFA is recommended to be 1:1–2:1 to balance their competing roles and achieve health benefits. Omega-6 and omega-3 PUFAs Omega-6 PUFAs, in the form of LA, are plentiful in most crop seeds and vegetable oils, such as canola, soybean, corn, and sunflower oils. In contrast to omega-6 PUFAs, omega-3 PUFAs are obtained from a limited range of dietary sources. Flax, chia, and perilla seeds are rich in ALA, with significant amounts also detected in green leafy vegetables. The consumption of fatty fish, such as salmon, sardines, tuna, trout, and herring, provides high amounts of EPA and DHA. Besides fish and their oils, small amounts of omega-3 PUFAs are also detected in red meat like beef, lamb, and mutton. All the above dietary sources provide EPA, DPA, DHA, LA, and ARA in different amounts, and their intake is necessary for normal physiological function. PUFAs play a critical role in many chronic diseases, affecting human cells by regulating inflammation, immune response, and angiogenesis. Omega-3 PUFAs’ role against hypertriglyceridemia has been clarified, and research indicates that systematically consuming oily fish can contribute to general heart protection. Supplementation with omega-3 PUFAs could potentially lower the risk of several cardiovascular outcomes, but the evidence is stronger for individuals with established coronary heart disease. Moreover, adequate EPA and DHA levels are necessary for brain anatomy, metabolism, and function. Although the mechanisms underlying omega-3 PUFAs' cardioprotective effects are still poorly understood, several studies have been conducted in this direction. Unfortunately, that does not hold true for their omega-6 counterparts, for which controversial emerging data tend to show anti-inflammatory behavior that needs to be further studied. Monounsaturated fatty acids (MUFAs) In contrast to PUFAs, monounsaturated fatty acids (MUFAs) are easily produced by the liver in response to the ingestion of carbohydrates. The main MUFA is oleic acid, found in plant sources, such as olive oil, olives, avocado, nuts, and seeds, while minimal amounts are also present in meat, eggs, and dairy products. Specific guidelines around MUFAs’ dietary consumption do not exist. Therefore, MUFAs are recommended to cover the remaining fat intake requirements to reach the total daily fat intake goal. A growing body of research shows that dietary MUFAs reduce or prevent the risk of metabolic syndrome, cardiovascular disease (CVD), and hypertension by positively affecting insulin sensitivity, blood lipid levels, and blood pressure, respectively. Moreover, olive oil contains several bioactive substances, possessing anti-tumor, anti-inflammatory, and antioxidant qualities. According to a meta-analysis, consuming olive oil was linked to a lower risk of developing any sort of cancer, especially breast cancer and cancer of the digestive system. Another study found that an isocaloric replacement of 5% of the energy from saturated fatty acids (SFAs) with plant MUFAs led to an 11% drop in cancer mortality over a 16-year follow-up period. Therefore, including MUFAs in the everyday diet offers multifaceted benefits in chronic disease prevention and management, including cancer and general health promotion.  Saturated fatty acids (SFAs) Saturated fatty acids (SFAs) form a heterogeneous group of fatty acids that contain only carbon-to-carbon single bonds. Whole-fat dairy, (unprocessed) red meat, milk chocolate, coconut, and palm kernel oil are all SFA-rich foods. These fatty acids have distinct physical and chemical profiles and varying effects on serum lipids and lipoproteins. Stearic, palmitic, myristic, and lauric acids are the principal SFAs found in most natural human diets. Dietary practice and guidelines recommend limiting SFA intake to <10% of the total energy (E%), while the American Heart Association suggests an even lower intake of <7 E% because total saturated fat consumption and LDL-C levels are positively correlated. However, the role of SFAs in CVDs is quite complex, and the evidence is heterogeneous. In a recent study with a 10.6-year follow-up period, which included 195,658 participants, there was no proof that consuming SFAs was linked to developing CVD while replacing saturated fat with polyunsaturated fat was linked to an increased risk of CVD. Moreover, according to 6 systematic reviews and meta-analyses, cardiovascular outcomes and total mortality were not significantly impacted by substituting saturated fat with polyunsaturated fat. Even if these analyses were to be challenged, due to heterogenous evidence, the possible reduction in CVD risk associated with replacing SFAs with PUFAs in several studies may not necessarily be an outcome of SFAs’ negative effect but rather a potential positive benefit of PUFAs. Regarding SFAs' effect on different types of cancers, associations of their intake with an increased risk of prostate and breast cancer have been indicated. Conversely, a meta-analysis showed no link between SFA intake and a higher risk of colon cancer; similarly, consuming MUFAs, PUFAs, or total fat did not affect colon cancer risk. Hence, the role of SFA consumption in preventing, promoting, or having a neutral role in serious chronic diseases has not been fully elucidated yet. Trans fatty acids (TFAs) Trans fatty acids (TFAs) are created industrially by partially hydrogenating liquid plant oils or can be naturally derived from ruminant-based meat and dairy products. TFAs are highly found in commercial baked goods, biscuits, cakes, fried foods, etc. Guidelines regarding TFAs are stringent and limit TFA intake to <1% of energy or as low as possible. In 2015, the US Food and Drug Administration declared that industrial TFAs are no longer generally recognized as safe and should be eliminated from the food supply as their consumption is strongly linked to various CVD risk factors. Specifically, TFA intake raises triglycerides and increases inflammation, endothelial dysfunction, and hepatic fat synthesis, leading to a significantly increased risk of coronary heart disease (CHD). A meta-analysis suggested that increased TFA intake led to an increase in total and LDL-cholesterol and a decrease in HDL-cholesterol concentrations. Data also indicates that TFAs may influence carcinogenesis through inflammatory pathways, but the reported data are debatable. A recent study investigated the effects of all types of dietary fat intake on CVD risk. While PUFA, MUFA, and SFA intake were not linked to higher CVD risk, dietary TFA intake showed a strong association with CVD risk. Analysis indicated PUFA intake and CVD risk were inversely correlated, and the relative risk of CVD was reduced by 5% in studies with a 10-year follow-up. Dietary lipids and the human microbiome Dietary lipids also affect human microbiota composition. Studies have identified a close association between the human microbiome and metabolic diseases, including obesity and type 2 diabetes. Diets with a high omega-6 PUFA, SFA, and TFA intake increase the amount of many detrimental bacteria in the microbiome and reduce the amount of the beneficial ones, altering the microbiota composition and inducing inflammation via the secretion of pro-inflammatory cytokines. These bacteria may disrupt the gut barrier function, allowing lipopolysaccharides (LPS) translocation, which are bacterial toxins. This condition is linked to metabolic perturbations such as dyslipidemia, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and CVD. On the contrary, omega-3 PUFA (EPA and DHA) supplementation increases beneficial bacteria and limits harmful ones, enhancing intestinal barrier functioning and preventing LPS translocation and its implications. Omega-3 PUFA supplementation has also been studied as a means of mental health disorders management, but the evidence is still controversial. A possible protective impact of fish consumption on depression has been suggested by various studies, as well as a possible protective effect of dietary PUFAs on moderate cognitive impairment. A recent review of meta-analyses indicated that omega-3 PUFA supplementation might have potential value in mental health disorders, but data credibility is still weak. Dietary lipids and obesity Last but not least, obesity and its management is another field that dietary lipids intake seems to impact with their mechanisms. A diet high in PUFA has been shown to lower the total mass of subcutaneous white adipose tissue (the predominant fat type in human bodies), reduce blood lipid levels, and improve insulin sensitivity. In a study comparing PUFA and MUFA isocaloric intake, PUFA was more advantageous and lowered visceral adiposity in patients with central obesity. By stimulating brown adipose tissue, which aids energy expenditure through its elevated thermogenic activity, omega-3 PUFAs seem to elicit these positive effects in fat tissue, thus being useful in preventing and/or managing obesity. Another related study compared PUFA to SFA overfeeding in dietary surplus conditions that aimed to increase weight by 3%. While SFA overfeeding led to weight gain, primarily through the expansion of the visceral adipose tissue, PUFA overfeeding also led to weight gain, but because of a greater expansion of lean tissue mass. To sum up, dietary fats are an essential part of the human diet with many important physiologic functions, including cell function, hormone production, energy, and nutrient absorption. Moreover, dietary fat consumption is associated with positive outcomes in regard to cardiovascular disease, metabolic syndrome, cancer, and depression. Therefore, there is no reason to demonize this valuable dietary component, incriminating it for irrelevant adverse health outcomes, primarily weight loss failure and obesity. References 1. Astrup A, Magkos F, Bier DM, Brenna JT, de Oliveira Otto MC, Hill JO, King JC, Mente A, Ordovas JM, Volek JS, Yusuf S, Krauss RM. Saturated fats and health: A reassessment and proposal for food-based recommendations: JACC State-of-the-Art review. J Am Coll Cardiol. 2020;76(7):844-857. DOI: 10.1016/j.jacc.2020.05.077 2. Bojková B, Winklewski PJ, Wszedybyl-Winlewska M. Dietary fat and cancer-Which is good, which is bad, and the body of evidence. Int J Mol Sci. 2020;21(11):4114. DOI: 10.3390/ijms21114114 3. Custers, Emma EM, Kiliaan, Amanda J. Dietary lipids from body to brain. Prog Lipid Res. 2022;85:101144. DOI: 10.1016/j.plipres.2021.101144 4. de Souza RJ, Mente A, Maroleanu A, Cozma AI, Ha V, Kishibe T, Uleryk E, Budylowski P, Schünemann H, Beyene J, Anand SS. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ. 2015;351:h3978. DOI: 10.1136/bmj.h3978 5. Gao X, Su X, Han X, Wen X, Cheng C, Zhang S, Li W, Cai J, Zheng L, Ma J, Liao M, Ni W, Liu T, Liu D, Ma W, Han S, Zhu S, Ye Y, Zeng F-F. Unsaturated fatty acids in mental disorders: An umbrella review of meta-analyses. Adv Nutr. 2022;13(6):2217-2236. DOI: 10.1093/advances/nmac084 6. Liu AG, Ford NA, Hu FB, Zelman KM, Mozaffarian D, Kris-Etherton PM. A healthy approach to dietary fats: understanding the science and taking action to reduce consumer confusion. Nutr J. 2017;16(1):53. DOI: 10.1186/s12937-017-0271-4 7. Poli A, Agostoni C, Visioli F. Dietary fatty acids and inflammation: Focus on the n-6 series. Int J Mol Sci. 2023;24(5):4567. DOI: 10.3390/ijms24054567 8. Saini RK, Keum Y-S. Omega-3 and omega-6 polyunsaturated fatty acids: Dietary sources, metabolism, and significance-A review. Life Sci. 2018;203:255-267. DOI: 10.1016/j.lfs.2018.04.049 9. Saini RK, Prasad P, Sreedhar RV, Naidu KA, Shang X, Keum Y-S. Omega-3 polyunsaturated fatty acids (PUFAS): Emerging plant and microbial sources, oxidative stability, bioavailability, and health benefits-A review. Antioxidants (Basel). 2021;10(10):1627. DOI: 10.3390/antiox10101627 10. Zhao M, Chiriboga D, Olendzki B, Xie B, Li Y, McGonigal LJ, Maldonado-Contreras A, Ma Y. Substantial increase in compliance with saturated fatty acid intake recommendations after one year following the American Heart Association diet. Nutrients. 2018;10(10):1486. DOI: 10.3390/nu10101486 11. Zhu Y, Bo Y, Liu Y. Dietary total fat, fatty acids intake, and risk of cardiovascular disease: a dose-response meta-analysis of cohort studies. Lipids Health Dis. 2019;18:91. DOI: 10.1186/s12944-019-1035-2
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