This is the fifth and final installment of our series of articles that covered the world of longevity and explored the various pathways that intertwine lifespan and healthspan. This article will focus on the crucial role of metabolic health in pursuing a longer and healthier life.
Metabolic health stands as an essential pillar of longevity, encompassing not only traditional indicators such as insulin sensitivity and lipids but also groundbreaking factors like inflammatory cytokines found in the blood. By examining Lipids and ApoE, Parabiosis, Adipokines and myokines, Cortisol, Insulin, blood sugar, and Inflammation, we’ll get a better understanding of the intricate relationship between metabolic well-being and aging.
This is the fifth article in our five part “The Pathways of Aging” series, where we introduce the most important pathways and concepts in aging research. Each article addresses a major category according to the underlying biology.
- Growth Pathways and Nutrient Sensing
- Resilience to Molecular Damage and Stress
- Repair and Recycling
- Rejuvenation of Cells, Tissues, and Stem Cells
- Metabolic Health
Table of Contents
The Impact of LDL Cholesterol and ApoE on Longevity and Healthspan
Both LDL cholesterol and the cholesterol-carrier protein ApoE have a tremendous impact on lifespan and healthspan. Over the years, many studies confirmed that lowering LDL cholesterol can reduce the incidence of cardiovascular disease. Still, it was only recently that studies utilizing a modern genomics approach also showed that genetically predicted lower LDL is associated with longer lifespans (Daghlas et al. 2021).
Maybe even more important but less well-understood is the connection between ApoE and longevity. The human ApoE gene comes in three flavors — ApoE2, ApoE3, or ApoE4 — which are also called genetic alleles. It is the most robust longevity gene so far identified in humans. Carriers of the E4 allele have an elevated risk of Alzheimer’s disease and tend to be shorter-lived, whereas the E2 allele is generally protective (Deelen et al. 2019, Neu et al. 2017). While the biology of ApoE remains poorly understood, there are nonetheless indications that lipid-lowering, physical activity, and diets rich in omega-3 fatty acids can offset the deleterious effects of having an ApoE4 allele (Bos et al. 2019).
Young Blood, Old Blood: The Effects of Parabiosis on Healthspan
Not long ago, researchers at Stanford made the stunning discovery that if you link up the blood circulation of a young and an old mouse, this has beneficial effects on the health of the older animal, leading to partial rejuvenation (Conboy et al. 2013).
Although the mechanism is still speculative, several hypotheses have been advanced. Parabiosis may work through the transfer of health-promoting factors from the young animal (e.g. BDNF, FGF21, adiponectin, etc.) or alternatively via the dilution of harmful factors in the blood of the old animal (e.g., inflammatory cytokines, iron, and others). In recent years, the latter explanation has gained popularity (Mehdipour et al. 2020).
The Link Between Adipose Tissue and Muscle: Adipokines and Myokines Explored
Adipokines are factors secreted by fat (adipose) tissue. The two most famous adipokines are leptin and adiponectin. The latter is secreted by healthy adipose tissue and promotes insulin sensitivity. Weight loss in humans and life-extending growth hormone deficiency in mice increase circulating adiponectin levels (Salehi-Abargouei et al. 2015, Miller et al. 2017).
In analogy to adipokines, myokines are factors secreted by muscle. Two of the more interesting myokines are FGF21 and brain-derived neurotrophic factor (BDNF). The latter is particularly intriguing because BDNF levels decrease with age (Zagrebelsky et al. 2020), and restoration of BDNF levels through gene therapy increases the health span of mice (McMurphy et al. 2019). The secretion is promoted by exercise, particularly resistance training like weight lifting (Zhou et al. 2022), and intermittent fasting in animal models.
Stress and Longevity: The Impact of Cortisol on Muscle, Skin, and Cardiovascular Health
Cortisol is famously known as a stress-induced hormone, and excessive amounts of cortisol contribute to muscle loss and skin breakdown. However, as we have recently discovered, there are good types of stress (eustress) and bad types of stress. Mild or temporary stress can be beneficial via so-called hormesis.
Thus it should come as no surprise that mildly elevated cortisol levels are seen with caloric restriction both in mice and, temporarily, with fasting in humans (Stewart et al. 2005, Nakamura et al. 2016). Intriguingly, vitamin C, as found in Novos Core, can modulate the cortisol-mediated stress response (Hooper et al. 2016), and this may be beneficial because elevated cortisol is associated with cardiovascular disease (Crawford et al. 2019).
Insulin Sensitivity and its Significance for Extending Lifespan
When we ingest carbohydrates and simple sugars, the pancreas produces insulin, which is a hormone that helps cells utilize the sudden influx of sugar effectively. Efficient secretion of insulin is necessary because excessive amounts of blood sugar are harmful, as they can damage tissues through the production of crosslinks like advanced glycation end products (AGEs, Maillard reaction), one of the twelve causes of aging. When the pancreas is forced to produce large amounts of insulin to normalize blood sugar, this can eventually contribute to beta cell exhaustion – the cells that produce insulin – and type II diabetes.
The ability to effectively handle a high sugar load with a low amount of secreted insulin is called insulin sensitivity. Although high insulin sensitivity and low blood sugar levels are definitely health-promoting, they may be less important for lifespan extension than we initially thought (Nelson et al. 2012).
Inflammation and Aging: Connecting the Dots for Better Health
Overt inflammation is the body’s natural response to infection and local tissue damage. It is easy to spot, as it is characterized by the famous triad of redness, swelling, and pain (calor, rubor, dolor in latin). However, what is harder to see is so-called sterile inflammation, which is a low-level inflammatory state that increases with age.
This pathology is considered one key driver of aging, and sometimes this is also called “inflammaging.” Inflammation can be measured from a blood panel, looking at, for example, CRP (c-reactive protein), TNFa, and IL-6, all of which are associated with age-related diseases in people (Soysal et al. 2016, Varadhan et al. 2014).
Recent studies have shown that senescent cells are a major contributor to inflammation, which can be alleviated by the anti-aging compounds rapamycin and fisetin, or NOVOS Core, which contains fisetin and has been shown in a human in vitro study to keep senescent cells at bay (Wang et al. 2017, Yousefzadeh et al. 2018).
In people, the CANTOS trial provides proof of concept that reducing inflammation can prevent cardiovascular disease (Koenig 2017), and it is hoped that this solution will also translate to other age-related diseases.
Aging and Longevity: Pathways to Health and Vitality
In this comprehensive exploration of aging and longevity, we’ve journeyed through the intricate pathways that govern the aging process. From metabolic health and the significance of LDL cholesterol and ApoE to the groundbreaking discoveries of parabiosis and the potential of adipokines and myokines, each piece of the puzzle has shed light on the complexities of aging.
As we conclude this series, we recognize the vital connections between lifestyle, genetics, and the aging process. A multifaceted approach involving healthy habits, cutting-edge research, and potential interventions may unlock new doors to prolonging healthspan and aging gracefully.
The field of longevity research continues to evolve. As we embark on new scientific endeavors, we remain hopeful that innovative solutions will emerge, offering us a future where age becomes just a number and living life to the fullest becomes an enduring reality. NOVOS will remain on the cutting edge, delivering you the safest, most powerful, and proven solutions available.
Kamil Pabis, MSc is an aging researcher and longevity advocate with several years of experience in the aging field that spans multiple countries. Among other projects, Kamil worked on long-lived dwarf mice in Austria, on mitochondrial disease and aging in the UK, and finally on the bioinformatics of aging in Germany and Singapore. Presently, he is involved in several projects related to science communication and translational aging research.
References – Lipids and ApoE
Daghlas, Iyas, and Dipender Gill. “Low‐density lipoprotein cholesterol and lifespan: A Mendelian randomization study.” British Journal of Clinical Pharmacology 87.10 (2021): 3916-3924.
Neu, Scott C., et al. “Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis.” JAMA neurology 74.10 (2017): 1178-1189.
Deelen, Joris, et al. “A meta-analysis of genome-wide association studies identifies multiple longevity genes.” Nature communications 10.1 (2019): 1-14.
Bos, Maxime M., et al. “The ApoE ε4 isoform: can the risk of diseases be reduced by environmental factors?.” The Journals of Gerontology: Series A 74.1 (2019): 99-107.
References – Parabiosis
Mehdipour, Melod, et al. “Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin.” Aging (Albany NY) 12.10 (2020): 8790.
Conboy, Michael J., Irina M. Conboy, and Thomas A. Rando. “Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity.” Aging cell 12.3 (2013): 525-530.
References – Adipokines and myokines
Salehi-Abargouei, A., V. Izadi, and L. Azadbakht. “The effect of low calorie diet on adiponectin concentration: a systematic review and meta-analysis.” Hormone and metabolic research 47.08 (2015): 549-555.
Miller, Karl N., et al. “Aging and caloric restriction impact adipose tissue, adiponectin, and circulating lipids.” Aging cell 16.3 (2017): 497-507.
Zagrebelsky, Marta, Charlotte Tacke, and Martin Korte. “BDNF signaling during the lifetime of dendritic spines.” Cell and tissue research 382.1 (2020): 185-199.
McMurphy, Travis, et al. “Hypothalamic gene transfer of BDNF promotes healthy aging in mice.” Aging Cell 18.2 (2019): e12846.
Seidler, Karin, and Michelle Barrow. “Intermittent fasting and cognitive performance–Targeting BDNF as potential strategy to optimise brain health.” Frontiers in Neuroendocrinology 65 (2022): 100971.
Zhou, Bojun, et al. “Effects of different physical activities on brain-derived neurotrophic factor: A systematic review and bayesian network meta-analysis.” Frontiers in aging neuroscience 14 (2022).
References – cortisol
Hooper, Michael H., Anitra Carr, and Paul E. Marik. “The adrenal-vitamin C axis: from fish to guinea pigs and primates.” Critical Care 23.1 (2019): 1-2.
Nakamura, Yuko, Brian R. Walker, and Toshikazu Ikuta. “Systematic review and meta-analysis reveals acutely elevated plasma cortisol following fasting but not less severe calorie restriction.” Stress 19.2 (2016): 151-157.
Crawford, Andrew A., et al. “Morning plasma cortisol as a cardiovascular risk factor: findings from prospective cohort and Mendelian randomization studies.” European journal of endocrinology 181.4 (2019): 429-438.
Stewart, Jeanne W., et al. “Prevention of mouse skin tumor promotion by dietary energy restriction requires an intact adrenal gland and glucocorticoid supplementation restores inhibition.” Carcinogenesis 26.6 (2005): 1077-1084.
References – Insulin and blood sugar
Nelson, James F., et al. “Probing the relationship between insulin sensitivity and longevity using genetically modified mice.” Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 67.12 (2012): 1332-1338.
References – inflammation
López-Otín, Carlos, et al. “The hallmarks of aging.” Cell 153.6 (2013): 1194-1217.
Wang, Rong, et al. “Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism.” Aging cell 16.3 (2017): 564-574.
Koenig, Wolfgang. “Inflammation revisited: atherosclerosis in the post-CANTOS era.” European Cardiology Review 12.2 (2017): 89.
Soysal, Pinar, et al. “Inflammation and frailty in the elderly: a systematic review and meta-analysis.” Ageing research reviews 31 (2016): 1-8.
Varadhan, Ravi, et al. “Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults.” Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 69.2 (2014): 165-173.