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History and mechanisms of this calorie restriction mimic that promotes autophagy
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Ageing is caused by accumulated molecular and cellular damage over time, leading to a decline in physical and mental capacity and an increased risk of disease and death (World Health Organisation, 2022). Several factors responsible for ageing include genetic instability, mitochondrial dysfunction, and stem cell exhaustion.
Ageing can be attributed to factors such as exposure to toxic chemicals, UV irradiation, physical trauma, and intrinsic factors like mutation, accumulation of reactive oxygen species (ROS), and protein folding. Ongoing research seeks to mitigate the impact of these factors and potentially eliminate them, but identifying the interconnectedness between hallmarks and their relative contributions to ageing is a significant challenge. (López-Otín et al.,2013)
To determine if an intervention can slow down the ageing process, it must be able to reduce the negative changes that occur as we age and decrease the likelihood of death. If an intervention does not meet these criteria, it cannot be considered anti-ageing. This has caused confusion and misleading claims about labelled products. For example, some products may help reduce wrinkles but do not extend lifespan or slow ageing. Therefore, they cannot be considered anti-ageing. (João Pedro de Magalhães, 2014).
The mitochondrial free radical theory of ageing is a well-established hypothesis which suggests that mitochondria may play a role in the ageing process. Mitochondria, a cell's powerhouse, are important for generating energy but can also create highly reactive particles called reactive oxygen species (ROS).
The accumulation of ROS primarily causes age-related cellular dysfunction leading to cellular damage by interfering with other biomolecules. (Steele,2021) Some life-threatening diseases involved with ROS accumulation include cancer, Alzheimer's, and cardiovascular diseases. (Tan et al., 2018)
Antioxidants are a vital line of defence for our cells against the harmful effects of ROS. The mechanism by which an antioxidant attaches to a ROS can vary, depending on the type of antioxidant and the specific ROS involved.
One of the key antioxidants is Thioredoxin-1 (TRX-1), which works by scavenging free radicals, neutralising them and preventing them from causing damage to other molecules in our bodies.
However, the protective effects of TRX-1 can be reduced by a protein called thioredoxin-interacting protein (TXNIP). This protein inhibits the activity of TRX-1, allowing free radicals to cause more damage to the cells. TXNIP is a naturally occurring protein that is present in cells throughout the body. However, its levels and activity can be influenced by various factors, including age, diet, and exposure to environmental toxins.
Research has shown that as we age, the levels of TXNIP tend to increase in both human cells and certain animal species. In fact, fruit flies that produce more TXNIP have been found to have a shorter lifespan, suggesting that this protein may play an important role in the ageing process.
When the levels of TXNIP become too high, they can interfere with the body's natural antioxidant defences, leading to increased oxidative stress and the development of age-related diseases. Therefore, it is important to maintain the levels of TXNIP within a healthy range to prevent age-related diseases and promote healthy ageing. (Oberacker et al., 2018).
If the aforementioned scenario is accurate, it is plausible that the consumption of antioxidants may not lead to the intended benefits, as the effectiveness of such antioxidants may be inhibited by TXNIP. It is worth noting, however, that the research supporting this hypothesis was conducted using an animal model. Therefore, further investigation is required to determine whether these findings can be directly extrapolated to humans.
It is also important to note that the complete elimination of ROS from the body is not always advantageous, as ROS plays a crucial role in the normal functioning of the cardiovascular and immune systems. Inadequate levels of ROS can also give rise to health issues. Thus, maintaining a balanced level of ROS is vital for overall well-being.
Furthermore, the precise relationship between ageing and the contributing factors may be difficult to be determined. For example, ageing caused by overactivation of the NF-κB pathway, which can result from various factors such as chronic inflammation, infections, and genetic mutations, cannot be mitigated by excluding ROS alone.
Several other theories, like the Cross-Linking Theory, suggest that the binding of glucose to proteins leads to impairments in protein function, causing various age-related problems. The Neuroendocrine Theory proposes that age-related changes in the neuroendocrine system, particularly in the hypothalamus, resulting in a decline in the secretion and effectiveness of hormones (Physiopedia, 2022). ROS may not be actively involved in all the theories of ageing.
There is limited evidence to suggest that antioxidants are effective for anti-ageing purposes. While some research supports using antioxidant-rich diets and supplements, conflicting evidence exists. The Seven Countries Study carried out by Singh et al. concluded that the Indo-Mediterranean diet has better protective effects against CVD than other diets. The Indo-Mediterranean diet's diverse range of foods and high antioxidant content, including millets, porridge, beans, and spices, provides excellent anti-inflammatory and cardioprotective effects.
Similarly, a recent systemic review by Das et al., assessed whether a higher intake of antioxidants could lower all-cause mortality or cause-specific mortality in older populations. 22 studies, including 1,090,844 cases of mortality, were included in the analysis. The results were inconclusive, with some studies showing significant decreases, some with significant increases, and others showing no association between antioxidant intake and mortality risk.
João Pedro de Magalhães suggests that while supplements such as antioxidants may have health benefits, they do not necessarily delay ageing. Some supplements may be consumed in a purified form. However, they cannot substitute a balanced diet, as noted by many experts. For example, vitamin C supplementation can elevate vitamin C levels in the body. This alone cannot provide health benefits and is not a replacement for a diet rich in fruits and vegetables. Regular exercise, smoking cessation, and adequate hydration are equally essential factors to consider.
In summary, no single supplement can effectively halt the natural ageing process. While some studies suggest potential antioxidant benefits, conflicting evidence exists, and supplements may also have side effects.
Ultimately, the effectiveness of antioxidants may depend on the underlying cause of ageing. While supplements may help mitigate some age-related symptoms by promoting health, they cannot be a complete substitute.
While a diet abundant in antioxidants may provide some advantages, it cannot be considered the sole solution to anti-ageing. Excessive antioxidant levels in the body can eliminate ROS, which may have adverse effects. It is advisable to prioritise a healthy lifestyle over relying solely on supplements for longevity.
Blog written by Sanjana Gajbhiye
1. Ageing and health. (2022, October). World Health Organization
2. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of ageing. Cell, 153(6), 1194–1217
3. Anti-Aging Medicine: Current Therapies from the Science of Life-Extension. (2014). Senescence.info
4. Ageless – Andrew Steele. (2022, January 5). Andrew Steele
5.Tan, B. L., Norhaizan, M. E., Liew, W.-P.-P., & Sulaiman Rahman, H. (2018). Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases. Frontiers in Pharmacology
6. Oberacker, T., Bajorat, J., Ziola, S., Schroeder, A., Röth, D., Kastl, L., Edgar, B. A., Wagner, W., Gülow, K., & Krammer, P. H. (2018). Enhanced expression of thioredoxin-interacting-protein regulates oxidative DNA damage and ageing. FEBS Letters, 592(13), 2297–2307
7. Theories of Ageing. (2022). Physiopedia
8. Singh, R. B., Fedacko, J., Fatima, G., Magomedova, A., Watanabe, S., & Elkilany, G. (2022). Why and How the Indo-Mediterranean Diet May Be Superior to Other Diets: The Role of Antioxidants in the Diet. Nutrients, 14(4), 898
9. Das, A., Hsu, M. S. H., Rangan, A., & Hirani, V. (2020). Dietary or supplemental intake of antioxidants and the risk of mortality in older people: A systematic review. Nutrition & Dietetics, 78(1), 24–40
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Professor of Molecular Biogerontology at University of Birmingham Institute of Inflammation and Ageing, consultant, futurist, speaker
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