Supplements For Healthy Aging

Aging refers to structural and functional decline of an organism with time. With the improvement of medical levels and living standards, human beings are gradually moving towards an aging society. Whilst the lifespan in humans is increasing, healthspan (years spent in good health) is not. The incidence of cardiovascular diseases, Alzheimer’s and Parkinson’s diseases, muscular dystrophies is growing year by year; this means that more people are spending more years burdened by pain and illness. Gentle reminder: make sure to support the seniors around you, who may be lonely and in distress.

Strategies for combating mechanisms of aging to prevent disease is known as ‘geroprotection’ (Partridge et al., 2020) and there is an increasingly popular movement that celebrates aging well instead of demonizing it.

It is known that lifestyle interventions, like dietary changes and exercise retard age-related illnesses, but there’s an increasing interest in tackling the underlying aging processes as a preventative measure to age-related illness.

In this article, we will discuss several findings in the field of ‘geroprotection’.

Nicotinamide adenine dinucleotide (NAD+)

NAD+  is a dinucleotide that plays an important role many metabolic functions, such as energy metabolism (remember the good old Krebs cycle?) and redox homeostasis. NAD+ is needed for the functioning of hundreds of enzymes such as the poly (ADP-ribose) polymerase (PARP) enzymes which  plays a role in DNA repair. NAD+ is sole substrate for enzymes called sirtuins (SIRT1-7) which have shown remarkable abilities to prevent diseases and even reverse aspects of aging in many mammalian models.

In 2011, a study showed that NAD+ is an essential factor in the aging process and is in declining levels in catabolic tissue such as the brain, heart, lung, liver and kidney of rats, and in human pelvic tissue (Clement et al., 2019). It is also known that endogenous NAD+ pool is lower in several chronic and degenerative diseases (e.g., cardiovascular diseases, Alzheimer’s and Parkinson’s diseases, muscular dystrophies), and has also been shown to steeply decline with age in preclinical studies as well as small human studies.

Why does NAD+ deplete with age?

We know that NAD+ is involved in numerous pathways, so finding a single cause for depletion is difficult. One reason that has been documented in literature is related to the PARP1 enzyme. As we age, there is inevitably more DNA damage due to a number of stressors such as alcohol consumption, chronic inflammation and weight gain; We know that DNA damage activates the PARP1 enzyme, which uses up NAD+ in order to function. Thus, the pool of NAD+ becomes depleted.

NAD+ enhancer – Niacin

NAD+ is synthesised in the body from precursors in the diet, such the amino acid tryptophan (Trp) and niacin (Fig 1.). Niacin is a term used to describe compounds that directly contribute to the niacin status in the body. These are nicotinic acid (NA), nicotinamide (NAM) and related derivatives, such as nicotinamide riboside (NR). Niacin is found in muscle-based foods, like poultry and beef, as well as plant-based foods, like nuts and legumes.

According to the UK dietary guidelines, the daily consumption of niacin should be 13.2 mg of for women and 16.5 mg for men. Meeting these daily dietary nutrient requirements is important for optimal health.

Numerous clinical trials have now shown that high-dose supplementation with niacin can boost endogenous NAD+ levels in humans.

Because NAD+ cannot be taken up by cells directly, in supplementation studies it is the NR and NAM precursors that are most commonly used. Supplementation of NAD+ precursors at high doses has been shown to ameliorate many in age-related cellular impairments in animal models as well as adults. A 2019 randomised control trial supplemented twelve 70-80 year olds with NR at doses of 1 g/d for 3 weeks (Elhhassan et al., 2019). The intervention trial found NR supplementation to be well-tolerated and safe. It also increased NAD+ synthesis in skeletal muscle. A 2020 randomised control trial on healthy obese individuals obtained similar findings after NR supplementation for 6wk increased NAD+ synthesis in skeletal muscle (Remie et al., 2020).

Since age-related NAD+ depletion has been linked to numerous degenerative diseases which negatively affect quality of life at older age, the results of the mentioned randomised control trials are exciting. It may be that endogenous NAD+ levels can be restored to the more ‘youthful’ levels with natural supplements, like NR, improving wellbeing for the increasingly aging population.

Since high-dose niacin intervention is not yet part of conventional clinical practice, always consult your doctor before starting a supplementation regime.

NAD+ enhancer – Resveratrol

Resveratrol is a polyphenol naturally found in grapes. In vitro and animal studies have long suggested resveratrol to improve health and prevent chronic disease. It has been linked to many health benefits mediated through its antioxidant, anti-inflammatory, cardio-protective, and neuro-protective activities. A 2011 review of available literature from human trials agreed with pre-clinical data, especially in patients with compromised health. The review went on further to suggest that healthy individuals may also benefit from “resveratrol’s potential to delay or prevent age and lifestyle induced decrements in health” (Smoliga et al., 2011). Since this study was commissioned by a resveratrol supplement manufacturer, its evidence is taken with caution.

Since 2011, several studies have now shown resveratrol to indirectly stimulate NAD+ production (Fig. 1) by activating the energy sensor AMP-activated protein kinase (AMPK). A 2015 clinical study found low dietary achievable doses of resveratrol doses to enhance AMPK activation in colorectal cancer tissue in human patients (Cai et al., 2015). Resveratrol supplementation has also shown to mimic the effects of calorie restriction (Fig. 1) in healthy and slightly overweight individuals, significantly increasing the plasma levels of SIRT1, an enzyme associated with lifespan extension and other anti-aging effects in many animal models.

A recent meta-analysis of randomised control trials looked at the effects of resveratrol supplementation and oxidative stress. It found that resveratrol supplementation at 500-900 mg/d for 60 days increased the total antioxidant content (TAC) in the blood, which is sensitive and reliable marker “ of the ability of antioxidants present in the blood to protect against oxidative damage of cellular components” (Koushki et al., 2019). This is great news, since oxidative stress plays a role in the pathogenesis of many age-related illnesses, such as cancer and atherosclerosis. Another high quality meta-analysis looked at the effects of resveratrol supplementation on people at high risk of cardiovascular disease. The study found supplementation to reduce the total blood cholesterol, concluding that resveratrol supplementation may have cardioprotective effects.

It should be noted that most studies in this meta-analyses mentioned were carried out on people with compromised health, such as smokers, obese individuals or those with type-2 diabetes. Whilst resveratrol may be a good complementary supplement, lifestyle factors such as smoking, alcohol consumption, diet and exercise should be addressed primarily. Since high-dose resveratrol supplementation is not part of conventional clinical practice, always consult your doctor before starting a supplementation regime

Fig 1. Graph taken from Srivastava (2016) on PubMed. “The physiological and pharmacological interventions that boost NAD+ levels are highlighted in yellow and pink respectively whereas the pathways that produce and consume/decrease NAD+  levels are highlighted in green and red respectively” (Srivastava, 2016). (http://creativecommons.org/licenses/by/4.0/)

Collagen peptides

Collagen is the main structural protein in the various connective tissues such as skin and bone that makes up about 25% of the total dry weight of mammals and about 75% of skin’s dry weight. Collagen absorption is low, which is why collagen needs to be hydrolysed into peptides to become bioavailable.

Can you increase/improve collagen?

Nutritionally, collagen is poor-quality protein, since its amino acid composition is limited to three repeating amino acid units – glycine, proline, and hydroxylproline, which are non-essential amino acids. This means that they can be synthesised in the body from other sources. Just like all proteins, collagen is digested into amino acids and absorbed to make up the body’s amino acid pool. From this pool, amino acids are either synthesised into new proteins (if there is a demand) or degraded into ‘parts’ (if there is an excess) for excretion and/or energy metabolism.

In theory, as long as you consume sufficient amounts of high quality protein (to ensure you have the amino acids needed to meet your body’s demands for protein synthesis) your body should synthesise as much collagen as it requires.

Collagen and osteoarthritis

Osteoarthritis (OA) is one of the most common causes of disability which leads to poor quality of life especially in older generations. OA is a progressive disease that is caused by the loss of joint cartilage leading to joint damage. Knee joints are most frequently affected making mobility painful, therefore current non-surgical treatments are focused mainly of pain relief as well as inflammation mediation. In recent years, collagen supplementation has attracted interest as a potential treatment for OA. In fact, collagen supplementation has been shown to be an effective supplement for improving the symptoms of OA, according to a meta-analysis and systematic review published in 2018 (García-Coronado et al., 2018). The positive effects were attributed to the supplement’s potential to induce collagen regeneration and protection against damage.

Collagen and skin

There are different factors that lead to the deterioration in appearance and integrity of skin with age, with the loss of quantity and quality of dermal collagen leading to loss of elasticity and skin tone. In this process, skin creases deepen, forming wrinkles – a major sign on skin aging.

Skin aging is a complex process driven by two components; internal aging, such as reduced collagen expression, and extrinsic aging caused by environmental exposure, such as collagen degradation due to UV damage.

A simple way to slow extrinsic skin aging is by using high-quality UV protection daily. In terms of intrinsic aging, leading a healthy, balanced and active lifestyle is important for healthy aging. Moreover, numerous studies have revealed that collagen interventions can improve skin aging parameters such as skin moisture and elasticity. A recent systematic review of available research summarised the possible mechanisms for the beneficial effects of collagen supplementation. One hypothesis is related to the gut. The immune system samples the contents that pass through our gut lumen. The presence of collagen antigens in the gut lumen leads to the suppression of autoimmunity against collagen in the body and recovery of damaged tissue through collagen-mediated regulatory T-cells.

In many societies, we are much more health conscious now than we were 50 years ago. We now understand that although inevitable, aging is modifiable. We know that lifestyle factors such as a balanced diet and exercise already puts us on a path towards healthy aging.  On top of that, numerous of pharmacological interventions have shown promising clinical results, such as the natural compounds discussed in this article. So whilst the current healthspan statistics may seem bleak at first, the future looks very bright indeed!

References:

Akbari, M., Tamtaji, O.R., Lankarani, K.B., Tabrizi, R., Dadgostar, E., Haghighat, N., Kolahdooz, F., Ghaderi, A., Mansournia, M.A. and Asemi, Z. 2020. The effects of resveratrol on lipid profiles and liver enzymes in patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials. Lipids in health and disease. 19(1), pp.25-25.

Barati, M., Jabbari, M., Navekar, R., Farahmand, F., Zeinalian, R., Salehi-Sahlabadi, A., Abbaszadeh, N., Mokari-Yamchi, A. and Davoodi, S.H. 2020. Collagen supplementation for skin health: A mechanistic systematic review. 0(0), pp.1-10.

Chen, C., Zhou, M., Ge, Y. and Wang, X. 2020. SIRT1 and aging related signaling pathways. Mech Aging Dev. 187, p.111-215.

Clement, J., Wong, M., Poljak, A., Sachdev, P. and Braidy, N. 2019. The Plasma NAD(+) Metabolome Is Dysregulated in “Normal” Aging. Rejuvenation research. 22(2), pp.121-130.

Csiszar, A., Tarantini, S., Yabluchanskiy, A., Balasubramanian, P., Kiss, T., Farkas, E., Baur, J.A. and Ungvari, Z. 2019. Role of endothelial NAD(+) deficiency in age-related vascular dysfunction. Am J Physiol Heart Circ Physiol. 316(6), pp.1253-1266.

Custodero, C., Saini, S.K., Shin, M.J., Jeon, Y.K., Christou, D.D., McDermott, M.M., Leeuwenburgh, C., Anton, S.D. and Mankowski, R.T. 2020. Nicotinamide riboside—A missing piece in the puzzle of exercise therapy for older adults? Experimental Gerontology. 137, pp.110-972.

Elhassan, Y.S., Kluckova, K., Fletcher, R.S., Schmidt, M.S., Garten, A., Doig, C.L., Cartwright, D.M., Oakey, L., Burley, C.V., Jenkinson, N., Wilson, M., Lucas, S.J.E., Akerman, I., Seabright, A., Lai, Y.-C., Tennant, D.A., Nightingale, P., Wallis, G.A., Manolopoulos, K.N., Brenner, C., Philp, A. and Lavery, G.G. 2019. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Reports. 28(7), pp.1717-1728.

García-Coronado, J.M., Martínez-Olvera, L., Elizondo-Omaña, R.E., Acosta-Olivo, C.A., Vilchez-Cavazos, F., Simental-Mendía, L.E. and Simental-Mendía, M. 2019. Effect of collagen supplementation on osteoarthritis symptoms: a meta-analysis of randomized placebo-controlled trials. Int Orthop. 43(3), pp.531-538.

Jenkins, G. 2002. Molecular mechanisms of skin aging. Mechanisms of Aging and Development. 123(7), pp.801-810.

Koushki, M., Dashatan, N.A. and Meshkani, R. 2018. Effect of Resveratrol Supplementation on Inflammatory Markers: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clinical Therapeutics. 40(7), pp.1180-1192.

Koushki, M., Lakzaei, M., Khodabandehloo, H., Hosseini, H., Meshkani, R. and Panahi, G. 2020. Therapeutic effect of resveratrol supplementation on oxidative stress: a systematic review and meta-analysis of randomised controlled trials. Postgrad Med J. 96(1134), pp.197-205.

Partridge, L., Fuentealba, M. and Kennedy, B.K. 2020. The quest to slow aging through drug discovery. Nature Reviews Drug Discovery.

Rajman, L., Chwalek, K. and Sinclair, D.A. 2018. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab. 27(3), pp.529-547.

Smoliga, J.M., Baur, J.A. and Hausenblas, H.A. 2011. Resveratrol and health–a comprehensive review of human clinical trials. Mol Nutr Food Res. 55(8), pp.1129-1141.

Srivastava, S. 2016. Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders. Clinical and translational medicine. 5(1), pp.25-25.

Rusne Z

Rusne Z.

Rusne is a United Kingdom-based writer passionate about nutrition as treatment and prevention of illness. She is currently completing her Bachelor in Food Science and Nutrition at the University of Leeds, and has Research & Development experience in the reformulation of sugary soft drinks.

Apart from her studies, Rusne particularly enjoys cooking, travelling and exploring independent coffee shops.

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