Spermidine may slow aging

So what exactly is aging?

It is funny really, people talk about aging all the time, they complain about the aches and pains, wrinkles and the other things that accompany it and yet most people do not really understand what aging is. So before we discuss in detail the studies of spermidine let us first get a better understanding of what aging is. In order to understand aging we need to define what it is, this is actually quite simple.

According to science, aging is the accumulation of damage that the body cannot completely eliminate, due to the imperfections of its protection and repair system. Over time this damage accumulates, bodily functions begin to deteriorate and ultimately this leads to the diseases of old age. Cancer, stroke, type 2 diabetes, heart diseases, Alzheimer’s disease, osteoarthritis, osteoporosis and others are all the result of this process of gradual loss of function due to accumulating damage.

Aging is not a single process however, it is made up of a number of distinct and interconnected processes (1). Once you begin to understand these processes and how they relate to each other it becomes possible to see how compounds like spermidine may slow down the aging process by reducing the accumulation of damage.

Of course science does not fully understand the aging process yet and there is a lot of research to be done before we do. However we already know a great deal about the damage that aging causes which means we can start to develop therapies and take measures right now that address some of this damage. This could help us to maintain health as we grow older as well as potentially delay the onset of some age-related diseases.

As previously mentioned, aging is a series of interconnected processes, known as hallmarks, that play upon each other and amplify dysfunction as part of that interaction. The aging hallmarks are likely caused by these nine broad processes:

  • Genomic instability: Nuclear and Mitochondrial DNA damage.
  • Telomere attrition: Erosion of the protective caps on chromosomes.
  • Epigenetic alteration: Changes to gene expression from pro-youth to pro-aging in the cell causing loss of efficient function.
  • Loss of Proteostasis: Protein misfolding that leads to amyloid accumulation.
  • Deregulated nutrient sensing: Response to nutrient levels becomes dysfunctional and cells fail to regulate energy production, cell growth, and other crucial functions.
  • Mitochondrial dysfunction: Decline of cellular energy (ATP) production and an increase in oxidative stress.
  • Cellular senescence: Dysfunctional cells accumulate and are not removed by the body and send out toxic signals that poison nearby healthy cells.
  • Stem cell exhaustion: Reserves of stem cells run out leading to loss of tissue repair and upkeep.
  • Altered intercellular communication: The signalling environment between cells changes driving inflammation and causing cells to become dysfunctional.

Now we understand these processes it is easier to see how we might begin finding solutions to them. A healthy, independent and long life is a worthy goal and science is making progress in helping us all attain this in the future.

In the following article we are going to review some of the research studies and take a closer look at how spermidine affects these aging processes.

Can spermidine slow the aging process?

Effective interventions against aging will need to impact on or more the nine mentioned damages. Very few interventions thus far have been successful in doing so, dietary restriction and rapamycin that both influence deregulated nutrient sensing have enjoyed some level of success. Studies show that polyamines, in particular spermidine can influence a number of factors that contribute to aging.

As we discussed in our general presentation, spermidine are part of the polyamine family, these interact with negatively charged molecules, such as DNA, RNA and lipids. This varied range of molecules they can bind to makes polyamines very versatile and indeed they are involved a large range of processes from DNA stability, cell growth and proliferation and apoptosis(cell death). Polyamine metabolism is complex so we will be discussing not only spermidine, but also the other polyamines putrescine and spermine in this article.

Aging causes polyamine levels to decrease but it was not until fairly recently in the last few years that the effect of polyamines on the aging process has been explored and in particular the role of spermidine (2). A 2012 study by Pucciarelli et al. showed that spermidine levels in people between sixty and eighty years old were significantly lower than those of people aged fifty or below. However they also noted that people over ninety have levels closer to those seen in people in of fifty or less. This suggests that maintaining spermidine levels may improve longevity (3).

Research shows that polyamine levels can be increased in animals and humans be supplementing with or having a diet rich in spermidine (4-6). A number of foods are rich in spermidine such as grapefruit, rice bran, broccoli, soybeans, mushrooms and mature cheeses (7).
A study by Eisenberg et al. showed that yeast cells, nematode worms, fruit flies and human peripheral blood mononuclear cells exposed to spermidine have an increased lifespan (8).

Soda et al. showed that a diet rich in polyamines decreased mortality in mice in 2009 and again in 2013 (9-10). The authors also noted that the mice had thicker fur and were more active than control animals the same age in their 2009 study. The research team showed in their later study that aging triggers changes to DNA methylation in the Kidneys, this is part of the aging hallmark epigenetic alteration. A diet rich in polyamines was able to suppress these changes thus protecting the kidneys from glomerular atrophy.

Autophagy is the primary geroprotective mechanism of spermidine

Studies to date strongly suggest that the primary geroprotective mechanism of spermidine is its influence on autophagy. Autophagy (from the Ancient Greek αὐτόφαγος autóphagos, meaning « self-devouring » and κύτος kýtos, meaning « hollow ») is the regulated destructive process the cell uses to break down and dispose of dysfunctional cell components. Autophagy can be thought of as the cellular garbage disposal system of the cell. Poor autophagy is associated with a number of age-related diseases.

The studies by Eisenberg et al. showed that all animal models and cell lines they tested with spermidine saw rapidly induced autophagy. This increased in autophagy was seen in yeast, flatworms, fruit flies and mouse cells. However yeast, flatworms, fruit flies that had poor autophagy and were subsequently given spermidine did not experience an increase in their lifespan. This suggests that autophagy is crucial for spermidine to affect lifespan.

Spermidine induces autophagy independently of the typical pathways associated with aging such as the sirtuins, in particular SIRT1 and SIRT6, which are a well known influencer of longevity in multiple species. The other typical pathway associated with longevity is mTOR (mammalian target of rapamycin) and spermidine works independently of this pathway also. Spermidine induces autophagy via a different pathway as observed in HCT116 human colon cancer cells, yeast and flatworms (11).

Spermidine has been shown to affect the acetylation profiles of many proteins, many of these proteins are part of the autophagy pathway in humans. Spermidine triggers deacetylation in the cytosol and acetylation in the nucleus and thus spermidine influences epigenetic alteration one of the hallmarks of aging. Spermidine can also include short-term autophagy without transcription of new proteins. This ability of spermidine to influence age-related epigenetic changes is confirmed by Soda et al. where an increased polyamine intake inhibited age-associated alteration of global DNA methylation (12). DNA methylation changes change gene expression and induce age-related changes to cell function, inhibiting these changes is geroprotective. So we know that autophagy induced by changes to DNA methylation is the primary way spermidine works but it is not the only way in which it can influence lifespan.

Reducing inflammation may help slow aging

One of the typical characteristics of aging is the smoldering, chronic background of inflammation that inhibits tissue repair, damages cells and causes them to become dysfunctional or become senescent. This age-related inflammation plays a central role in the hallmark: altered intercellular communication and is often referred to as “inflammaging”. Chronic levels of inflammation are strongly associated with many age-related diseases such as osteoarthritis, heart disease and cancer. The majority of studies to date have dealt with the acute inflammation created by injury but they share common pathways to chronic inflammation so are of interest.

It has been observed that polyamine levels usually increase with inflammation as polyamines activate the production of anti-inflammatory cytokines and inhibit pro-inflammatory ones. Unfortunately as part of this process polyamine metabolism produces cytotoxic byproducts such as hydrogen peroxide which cause inflammation too. On the whole it appears that polyamines have a mostly anti-inflammatory effect (13).

Spermidine has been shown to modulate the immune response in microglial cells. Microglia are the primary effector cells during inflammatory responses in the central nervous system. When treated with spermidine they showed a decrease in proinflammatory cytokines after exposure to lipopolysaccharide (LPS) which provokes inflammation (14). Treatment with spermidine decreased levels of nitric oxide and prostaglandin E2 in a dose-dependent manner. Prostaglandin E2 (PGE-2) is released by the blood vessel walls in response to infection or inflammation that causes the brain to induce fever. In addition spermidine was able to reduce the expression of inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) both key players in the inflammatory response and a significant contributor to inflammaging.

The authors of the study suggest that the anti-inflammatory effect from spermidine is caused by the inhibition of NF-kB (a master regulator of the inflammatory response) leading to a decreased phosphorylation of Akt and MAPK. Akt, is a protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration. MAPK is a protein kinase involved in directing cellular responses to a range of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. MAPK regulates cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis. So if spermidine improves expression of both Akt and MAPK then this is again a potential basis for geroprotective action.

As previously noted, the studies here have focused on acute inflammatory reactions and not the chronic background inflammation that is inflammaging and more research is needed. However given that these types of inflammation share common pathways in particular excessive NF-kB activation and the same pro-inflammatory cytokines, it is fair to say that polyamines and in particular spermidine could potentially slow down aging via reduction of inflammation.

Lipid Metabolism

The role of lipid metabolism has emerged is being influential on health and lifespan in the last few years. A dysfunctional lipid metabolism can result in dire consequences for health and most likely lifespan. Inversely mutations that improve lipid metabolism such as those that increase the level of stored lipids or alter lipid profiles favourably are shown to increase lifespan. This strongly suggests lipid metabolism plays an important role in modulating lifespan and that spermidine levels have an influence on lifespan by regulating lipids.

The level of lipids is regulated by the preadipocytes into mature adipocytes and spermidine plays a key role in this process known as adipogenesis (15-16). Researchers in these studies exposed 3T3-L1 cells to α-difluoromethylornithine (DFMO) a potent inhibitor of polyamine production. This exposure completely halted adipogenesis and totally disrupted lipid metabolism. However treatment with spermidine was able to rescue the halted lipid metabolism by restoring the expression of gene expression key to the differentiation of preadipocytes and resuming adipogenesis. The rescued cells were able to accumulate far as well as the control cells that had not been treated with DFMO. The study also showed that spermidine analogues were also able to rescue cell growth arrest induced by longer periods of exposure to DMFO, although not all cells were restored to the level of the control group cells. This suggests that supplementation with spermidine could be very important for improving adipogenesis

Cell Growth and Apoptosis

There is no doubt that over time as we age cells increasingly fail to respond to appropriate growth or apoptosis (controlled cell death) signals. Dysfunctional response to signal of cell growth or cell death leads to tissue and organ failure.

If cells cease to respond to cell growth signals then tissue repair and upkeep begins to fail and wound healing and tissue integrity start to fail. If cells can no longer react to the signal to divide and replace lost cells in the local tissue this can only lead to an increasingly poorer ability to keep tissue and organs working. This contributes to the hallmark of aging: Stem cell exhaustion.

Polyamines help to regulate cell growth and death and they decline with age, this decrease likely plays a part in cellular aging and polyamine supplementation may help to reduce the impact of cellular aging. Polyamines are required for cell growth and inhibiting them causes cell growth arrest in mammalian cells (17-18). Researchers in these studies inhibited cell growth by depleting polyamines then rescued them by supplementing with spermidine so that cell growth resumed. They performed a genomic profiling of the cells depleted of polyamines and it showed that this arrest and resumption of cell growth was accompanied by changes to gene expression, in particular genes linked to transcription, DNA replication and cell cycle. Additionally, the study authors noted that the polyamine-depleted cells exhibited a change to the expression of genes known to activate during the cellular stress response. This stress response quickly ceased upon spermidine exposure and cell growth resumption.

As we age cells can fail to destroy themselves when they become damaged or have replicated too many times, these senescent cells accumulate and begin to send out pro-inflammatory cytokines and contribute to the chronic background inflammation known as inflammaging. Cells failing to enter apoptosis when appropriate actually contribute to two aging hallmarks: cellular senescence and also altered intercellular communication. Not only do they contribute to the smoldering chronic background of inflammation but they can also induce other nearby healthy cells to become senescent and dysfunctional as well.

Polyamines regulate apoptosis and necrosis, however, the relationship between polyamines and apoptosis is far from a simple affair. Polyamines have been reported to induce apoptosis as well as prevent it (19). The study by Landau et al. showed that depleting NIH3T3 cells of polyamines actually prevented apoptosis (20). Inversely polyamines can also induce the release of cytochrome c which is a precursor to apoptosis (21-22). Also as mentioned previously polyamines can produce toxic hydrogen peroxide as a by-product which can also activate cytochrome c.

Polyamines can also regulate necrosis. A 2011 study by Carmona-Gutierrez et al. suggested polyamines my work via cathepsin D (23). The main physiological functions of cathepsin D are the metabolic degradation of intracellular proteins, activation and degradation of polypeptide hormones and growth factors, activation of enzymatic precursors, processing of enzyme activators and inhibitors, brain antigen processing and finally, the regulation of programmed cell death. In yeast that overexpressed PEP4 (the yeast version of cathepsin D) there was an increase in lifespan and a reduction of necrosis. This reduction of necrosis was dependent on the synthesis of putrescine and spermidine but not spermine. Finally and perhaps most interestingly, the overexpression of PEP4 prevented the age-related fall in putrescine and spermidine levels.

What pathways does spermidine use?

So the big question is, what signalling pathways does spermidine trigger its geroprotective effects? Typical pathways associated with longevity include SIRT1, mTOR and AMPK, however these pathways are unlikely to be involved with spermidine. A lot of the positive effects of spermidine appear to be based around autophagy so the pathways that induce autophagy are the most likely targets of spermidine. SIRT1, mTOR and AMPK are not likely candidates here as SIRT1 is not required for activation of autophagy and spermidine does not change the phosphorylation status of mTOR, AMPK and their substrates. Also autophagy is controlled by other pathways including Foxo, the downstream effector of the insulin-like signalling (IIS) pathway which is part of the aging hallmark: deregulated nutrient sensing and is a known modulator of lifespan. Another likely pathway is MAPK as this pathway is directly involved in the regulation of autophagy and is known to interact with polyamines (24). Spermidine can alter the phosphorylation of some MAPKs and finally, the expression of transcription factors the targets of MAPKs have been shown to change with polyamine depletion and are restored when exposed to spermidine.


Taken together these studies suggest that spermidine and its related polyamines play a role in various aging mechanisms of aging and in particular autophagy. These mechanisms are also linked and can be modulated by spermidine to potentially slow down the aging process. Spermidine induces autophagy whose dysfunction leads to aging and age-related pathology. Autophagy then in turn modulates the lipid profile which alters membrane fluidity, its resistance to peroxidation, as well as lipid signalling. Spermidine is able to directly regulate cell growth both via its influence on initiation factors as well as via lipid metabolism during adipogenesis. And last but not least, spermidine and other related polyamines can directly reduce inflammation by inhibiting pro-inflammatory cytokines and activating anti-inflammatory signalling. It can also indirectly influence inflammation via the changes it makes to lipid metabolism as well indirectly via autophagy.



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