The Five Pillars of Longevity Research

by Brooklin White, MSNutrition

Nutrition is one of the most commonly debated subjects and often leads to confusion regarding what to eat and when to eat it. Because everyone eats, everyone feels they know enough to give advice about food. Fortunately, Dr. Valter Longo PhD, premier researcher, professor and director of the Longevity Institute at the University of Southern California has created a way to “filter out the noise” to provide a guide to accurate dietary information.

This filtering system has been coined by Dr. Longo as the “Five Pillars of Longevity Research” which is based on Longo’s studies and previous studies from various labs and clinicians around the world. The five pillars focus on key research areas that help determine whether certain nutrients are beneficial or detrimental to health. When dietary choices are based on all five of the pillars, they are unlikely to be contradicted by new findings (1).

The Five Pillars of Longevity Research Explained

  1. Basic research:

    Basic research on simple organisms (yeast, flies, worms, mice) is an integral starting point for nutrition research. These simple organisms help us understand the fundamental properties of larger organisms such as primates and humans and allow for more invasive testing, which is required before human trials. Without understanding how nutrients affect cellular function, aging, age-dependent damage and regeneration in these simple organisms, it is difficult to understand the type and amount of nutrients needed to optimize healthspan and longevity (1). This basic research is where every nutritional study begins.

  2. Epidemiological studies:

    This pillar identifies risk factors for certain health conditions within a defined population. For example, if a researcher hypothesizes that a high consumption of refined carbohydrates promotes abdominal fat, then epidemiological research should confirm that those who eat high amounts of refined carbohydrates have a high waist circumference and an increased risk for diabetes (1). A current example of epidemiological data is seen in countries who have recently adopted the western diet (high saturated fats, refined carbohydrates etc.) and are thus increasing the prevalence of central adiposity, BMI, heart disease and diabetes. Epidemiological studies are one of the most important pillars because they tie math and statistics into the field of nutrition.

  3. Randomized and controlled clinical trials:

    Hypotheses that show success in basic research should eventually be demonstrated in human trials to prove efficacy. For example, if a researcher was studying the effects of curcumin (turmeric) on cognition and had success in mice, a randomized control trial in humans would be conducted with a control group who takes a placebo and an intervention group who takes curcumin. The two groups would have certain biomarkers tested at the beginning of the trail and then after a certain timeframe, would be tested again to measure biochemical differences. Clinical trials are crucial in understanding the effect a particular nutrient or combination of nutrients have on the progression or reversal of a disease state.

    Clinical trials involving nutrition interventions however can be difficult to prove causation. It’s nearly impossible to conduct randomized controlled trials (the gold standard in proving causation) in the area of lifestyle medicine because there are so many confounding factors at play and it can be difficult for participants to follow strict diet regimens long term. The IRB (Institutional Review Board) for example, tends not to approve lifestyle clinical trials since they cannot modify one variable, such as what the impact a specific drug has on a disease. Nutritional studies tend to be correlational, meaning scientists interview populations to receive diet history and over a period of time, can correlate certain diets to disease progression.

    Nutrition studies often contradict each other. For example, some studies say withholding red meat is one of the keys to longevity while others support the consumption, why? Often the trick is to understand who the authors are behind the study and what their motives are. Also, is there an abundance of research that supports one argument and very little for the opposition? In the case of red meat, the answer is yes. At the end of 2019, an article was published by the Annals of Internal Medicine that supported the consumption of red meat as a part of a healthy lifestyle (2). Their reasoning was that there is a weak link in the data between red meat consumption and disease, when in fact they failed to provide adequate data supporting this argument. The American College of Cardiology, American Cancer Association and American Heart Association collectively refuted this article by reiterating the importance of cutting down on red meat consumption based on the abundance of information. Dr. Frank Hu, chair of the Department of Nutrition at Harvard’s T.H Chan School of public health noted, “The new red meat and processed meat recommendation was based on flawed methodology and a misinterpretation of nutritional evidence” (3) At the end of the day, food is complicated, people are complicated, and lifestyles are complicated, so it is crucial for nutrition research to find patterns and trust the experts in the field.  

    The difficulty of nutrition clinical trials makes it that much more important to look at nutrition research holistically. By looking at simple organisms who possess the same aging genes as humans, observational epidemiological studies, centenarian studies and complex systems, we can start to create strongly supported correlations between certain aspects of nutrition and human health. 

  4. Centenarian studies:

    After basic research, epidemiological data and clinical trials are established, there is often uncertainty surrounding whether a specific diet or nutrient is safe for long-term use and whether or not the diet can realistically be obtained long-term. This is when looking at centenarian cultures (those who have the highest amount of people living healthfully to and beyond 100 years of age) becomes ideal. Dan Buettner, author of The Blue Zones, talks in great detail regarding lifestyle habits centenarians have in common and how adopting those habits are likely beneficial at increasing healthspan and longevity. One example is diet – almost all of the Blue Zone communities eat a high percentage of vegetables, whole grains, healthy fats such as olive oil or avocados and a reduced amount of meat, refined carbohydrates and processed foods. Since these communities have adopted this dietary lifestyle for generations and continue to live healthfully into old age, it gives us the confidence to further recommend these foods and eating patterns.

  5. Studies of complex systems:

    This pillar originated from Dr. Longo’s fascination with physics and the need to simplify the intricacy of the human body. By looking at how complex systems such as cars and planes age, we can see how their loss of function and oxidation relate similarly to aging human organs and systems. For example, reactive oxygen species (ROS) are one of the main causes of aging in humans, plants, and complex systems. An example of oxidation through ROS is when we cut an apple or avocado, leave it on the counter, and come back to a slightly browner version. Another example is when cars are left in the junkyard for too long and become rusty due to metal oxidation. As for humans, we know that aging and high calorie diets reduce superoxide dismutase (SOD) activity, which is a predominant antioxidant found in our cells. In healthy cells, SOD helps clear the accumulation of superoxide which is a byproduct ROS created by the mitochondria in our cells. This reduction of SOD allows for higher amounts of superoxide and thus more oxidative damage in our cells (4).

The Five Pillars Put to Practice

Hypothesis: Obesity is linked to reduced brain function.

Pillar 1: Basic Research Studies

  • According to Hwang et al., mice who were obese and maintained a high saturated diet from weaning to 12 months showed diabetes-like metabolism. The mice showed impaired learning and impaired long-term potentiation (LTP is a measurement of synaptic strength in the hippocampus which is the organ responsible for learning and memory) (5). LTP circuitry is normally high in young animals and decreases rapidly as we age.
  • Porter et. al also demonstrated that obese mice had impaired LTP (6).
  • Stranahan et al. showed that obesity reduced neurogenesis (the process by which neurons are developed in the brain) as the obese mice had 50% less new neural stem cells than the non-obese control mice (7). 

Pillar 2: Epidemiological Studies

  • Hou et al. found that abdominal obesity, as defined by waist-hip ratios, were significantly associated with a higher risk in cognitive impairment in the Chinese elderly (8).
  • Liu et al. was also able to demonstrate that abdominal obesity in Chinese adults was associated with an increased risk of cognitive decline (9).
  • Cherbuin et al. showed that in a population of Australian adults obesity was associated with lower hippocampal columns at baseline assessments and there was a significant hippocampal atrophy over time (10).

Pillar 3: Clinical Trial studies 

  • Clinical studies have shown that obesity as assessed by BMI, is associated with reduced gray matter volume in the hippocampus in both neurologically healthy and cognitively impaired older adults (11)(12). Gray matter consists of neuronal bodies and thus the loss of gray matter is associated with reduced memory and learning. 
  • The decrease in gray matter that is seen in obese adults is analogous to the loss in gray matter in individuals with Mild Cognitive Impairment and Alzheimer’s Disease. 

Pillar 4: Centenarian Studies 

  • We can also find the answer to this hypothesis when we ask the question in reverse, “When individuals are not obese, is there a lower prevalence of cognitive decline?” In Blue Zone communities, such as Ikaria, Greece, Alzheimer’s Disease among individuals over 85 is extremely rare as it is 75% less common than it is in the United States. Coincidentally, obesity, type 2 diabetes, depression, and cardiovascular disease are also quite rare (13). 
  • These centenarian populations found in the coastal areas of Costa Rica, Greece, Italy, Japan and California are considered longevity hotspots due to their healthy lifestyles. They eat mostly plants and fish while limiting their consumption of meat, dairy and overall calories. They grow their own garden and work outside frequently. They spend time with family and have strong spiritual connections. This lifestyle, therefore, permits an extremely low prevalence of obesity and other chronic diseases, such as Alzheimer's disease (14). 

Pillar 5: Complex Systems

  • As mentioned above, we know from research that oxidation by ROS is one of the key aspects contributing to loss of function in inanimate objects like cars, and animate organisms like plants and humans. Since adipose tissue is a hormonally active tissue and the largest endocrine organ in the body, when there is a large increase in fat deposits, it increases levels of pro-inflammatory cytokines (proteins involved in signaling) such as C-Reactive Protein (CRP), Interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) (15). Adipokines (cytokines of the adipose tissue) also induce the production of ROS which suggests that ROS and inflammatory markers are strongly correlated (16).  Research has indicated that this same inflammation is associated with neurodegeneration. For example, higher levels of CRP measured at mid-life in Japanese-American men was associated with an increased risk of Alzheimer’s disease (17).

    The increasing prevalence of Alzheimer's Disease in America is following the trend of increasing obesity. From 1999/2000 to 2017/2018, the age-adjusted prevalence of obesity increased from 30.5% to 42.4% (18). The number of people living with Alzheimer’s disease is currently 5.8 million, which is projected to triple to 14 million by 2060 (19). Although more research is underway to support this hypothesis, the Five Pillars of Longevity Research gives us a strong indication that there is a correlation between obesity and cognitive function.  

Research at the Amos Institute

It is crucial to look at nutrition research holistically and consider the source. Registered Dietitian Nutritionists (RDN) who are trained in functional medicine are the most qualified health professionals to seek information regarding accurate nutrition science. These dietitians undergo extensive training to understand the fundamentals of the human body and nutrition science, including those founded in basic research, epidemiological data, clinical trials and centenarian studies. Our functional medicine trained dietitians at the Amos Institute understand the importance of utilizing the Five Pillars of Research in order to provide the most up to date information for our clients. 

At the Amos Institute, not only do we take care to fully understand the existing body of scientific research, but we participate in the creation of new research. Of note, the Amos Institute published in the Journal of Alzheimer's Disease and Parkinsonism along with Dr. Dale Bredesen and other functional medicine practitioners showcasing the reversal of cognitive decline in 100 patients. 

For a look at our most recent publication, check out our post about our article published in the Journal of the American College of Nutrition about therapeutic uses of hibiscus in treating common chronic diseases which we published in January 2021.


  1. Longo, V. (2018). The longevity diet: Discover the new science behind stem cell activation and regeneration to slow aging, fight disease, and optimize weight. Penguin Random House.
  2. Johnston, B. C., Zeraatkar, D., Han, M. A., Vernooij, R. W. M., Valli, C., El Dib, R., Marshall, C., Stover, P. J., Fairweather-Taitt, S., Wójcik, G., Bhatia, F., de Souza, R., Brotons, C., Meerpohl, J. J., Patel, C. J., Djulbegovic, B., Alonso-Coello, P., Bala, M. M., & Guyatt, G. H. (2019). Unprocessed Red Meat and Processed Meat Consumption: Dietary Guideline Recommendations From the Nutritional Recommendations (NutriRECS) Consortium. Annals of Internal Medicine, 171(10), 756–764.
  3. Harvard Health Publishing. (2020, February). What’s the beef with red meat? Harvard Health.
  4. Szeto, H. H. (2006). Mitochondria-targeted peptide antioxidants: Novel neuroprotective agents. The AAPS Journal, 8(3), E521–E531.
  5. Hwang, L.-L., Wang, C.-H., Li, T.-L., Chang, S.-D., Lin, L.-C., Chen, C.-P., Chen, C.-T., Liang, K.-C., Ho, I.-K., Yang, W.-S., & Chiou, L.-C. (2010). Sex Differences in High-fat Diet-induced Obesity, Metabolic Alterations and Learning, and Synaptic Plasticity Deficits in Mice. Obesity, 18(3), 463–469.
  6. Porter, W. D., Flatt, P. R., Hölscher, C., & Gault, V. A. (2013). Liraglutide improves hippocampal synaptic plasticity associated with increased expression of Mash1 in ob/ob mice. International Journal of Obesity, 37(5), 678–684.
  7. Stranahan, A. M., Arumugam, T. V., Cutler, R. G., Lee, K., Egan, J. M., & Mattson, M. P. (2008). Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nature Neuroscience, 11(3), 309–317.
  8. Hou, Q., Guan, Y., Yu, W., Liu, X., Wu, L., Xiao, M., & Lü, Y. (2019). Associations between obesity and cognitive impairment in the Chinese elderly: An observational study. Clinical Interventions in Aging, 14, 367–373.
  9. Liu, Z., Yang, H., Chen, S., Cai, J., & Huang, Z. (2019). The association between body mass index, waist circumference, waist-hip ratio and cognitive disorder in older adults. Journal of Public Health (Oxford, England), 41(2), 305–312.
  10. Cherbuin, N., Sargent-Cox, K., Fraser, M., Sachdev, P., & Anstey, K. J. (2015). Being overweight is associated with hippocampal atrophy: The PATH Through Life Study. International Journal of Obesity, 39(10), 1509–1514.
  11. Ho, A. J., Raji, C. A., Becker, J. T., Lopez, O. L., Kuller, L. H., Hua, X., Lee, S., Hibar, D., Dinov, I. D., Stein, J. L., Jack, C. R., Weiner, M. W., Toga, A. W., & Thompson, P. M. (2010) Obesity is linked with lower brain volume in 700 AD and MCI patients. Neurobiology of Aging, 31(8), 1326–1339.
  12. Raji, C. A., Ho, A. J., Parikshak, N. N., Becker, J. T., Lopez, O. L., Kuller, L. H., Hua, X., Leow, A. D., Toga, A. W., & Thompson, P. M. (2010). Brain structure and obesity. Human Brain Mapping, 31(3), 353–364.
  13. Blue Zones. (2018). Diet and Dementia: What Foods Increase or Decrease Alzheimer’s Risk?
  14. Mishra, B. N. (2009). Secret of Eternal Youth; Teaching from the Centenarian Hot Spots (“Blue Zones”). Indian Journal of Community Medicine : Official Publication of Indian Association of Preventive & Social Medicine, 34(4), 273–275.
  15. Whitmer, R. A. (2007, March 31). The Epidemiology of Adiposity and Dementia. Current Alzheimer Research.
  16. Hensley, K., Robinson, K. A., Gabbita, S. P., Salsman, S., & Floyd, R. A. (2000). Reactive oxygen species, cell signaling, and cell injury. Free Radical Biology and Medicine, 28(10), 1456–1462.
  17. Singh, V. K., & Guthikonda, P. (1997). Circulating cytokines in Alzheimer’s disease. Journal of Psychiatric Research, 31(6), 657–660.
  18. Centers for Disease Control and Prevention. (2020, February 27). Obesity is a common, serious, and costly disease. Centers for Disease Control and Prevention. 
  19. Matthews, K. A., Xu, W., Gaglioti, A. H., Holt, J. B., Croft, J. B., Mack, D., & McGuire, L. C. (2018). Racial and ethnic estimates of Alzheimer’s disease and related dementias in the United States (2015–2060) in adults aged≥ 65 years. Alzheimer’s & Dementia.