Review

Spermidine in health and disease

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Science  26 Jan 2018:
Vol. 359, Issue 6374, eaan2788
DOI: 10.1126/science.aan2788

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Having your longevity and eating too

Although caloric restriction has clear benefits for maximizing health span and life span, it is sufficiently unpleasant that few humans stick to it. Madeo et al. review evidence that increased intake of the polyamine spermidine appears to reproduce many of the healthful effects of caloric restriction, and they explain its cellular actions, which include enhancement of autophagy and protein deacetylation. Spermidine is found in foods such as wheat germ, soybeans, nuts, and some fruits and vegetables and produced by the microbiota. Increased uptake of spermidine has protective effects against cancer, metabolic disease, heart disease, and neurodegeneration.

Science, this issue p. eaan2788

Structured Abstract

BACKGROUND

As the world population ages, chronic diseases such as diabetes, cardiovascular disease, cancer, and neurodegeneration become ever more prevalent. Interventions that favor healthy aging would constitute powerful strategies with which to limit human diseases that have a broad socioeconomic impact. Fasting regimens such as intermittent fasting or dietary adaptations such as caloric restriction are among the few regimens that extend life and beneficially affect health in all tested model organisms, including rodents and nonhuman primates. However, few people seem capable of changing their dietary routines for extended periods. Thus, supplementation with caloric restriction mimetics (CRMs), which would pharmacologically mimic the beneficial effects of caloric restriction or fasting, has gained attention as an attractive and potentially feasible strategy. The naturally occurring polyamine spermidine, the abundance of which declines during the process of aging, has emerged as a well-tolerable CRM targeting various molecular and physiological age-associated adversities.

ADVANCES

Conceptually, healthy aging requires the retardation of multiple molecular and cellular alterations that drive the aging process and induce age-associated pathologies. These include genomic instability, epigenetic alterations, loss of protein degradation capacity (leading to neurodegeneration), deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, and chronic inflammation. Spermidine displays pleiotropic effects that include anti-inflammatory properties, antioxidant functions, enhancement of mitochondrial metabolic function and respiration, as well as improved proteostasis and chaperone activity. Many anti-aging effects of spermidine are causally connected to the capacity of this polyamine to induce cytoprotective autophagy. Autophagy ensures general cell homeostasis and proteostasis and is directly involved in the degradation of damaged, potentially toxic organelles and harmful protein aggregates, thus removing and recycling cytoplasmic material that otherwise would accumulate during aging. Consistently, extra supply of spermidine prolongs the life span across species in an autophagy-dependent manner and counteracts age-associated pathologies such as cardiovascular disease, neurodegeneration, and cancer. For instance, dietary spermidine supplementation ameliorates age-induced memory impairment in flies and protects from autoimmune-directed demyelination of neurons in a mouse model for multiple sclerosis. Spermidine also reduces the growth of transplantable tumors, stimulates anticancer immune surveillance in combination with chemotherapy, and suppresses tumorigenesis induced by chemical insults in mice. Moreover, elevated dietary polyamine uptake correlates with reduced cardiovascular and cancer-related mortality in human epidemiological studies. Because spermidine is already present in daily human nutrition, clinical trials aiming at increasing the uptake of this polyamine appear feasible.

OUTLOOK

Although spermidine induces autophagy and autophagy inhibition curtails many of the health-promoting effects of spermidine, additional mechanisms have been proposed to explain the beneficial effects of spermidine on aging. These potentially autophagy-independent mechanisms include direct antioxidant and metabolic effects on arginine bioavailability and nitric oxide (NO) production. However, it has not been formally determined whether these routes act in a completely autophagy-independent manner or are interrelated with autophagy (in an additive or synergistic way) (see the figure), and it will be important to define actionable molecular targets that explain the beneficial effects of spermidine in diverse pathophysiological settings. In this sense, it will also be of interest to explore synergisms of spermidine with other CRMs that initially act through different mechanisms.

Another unresolved enigma resides in the tissue specificity of spermidine-induced health effects. For instance, the mechanisms through which oral spermidine intake can mediate systemic effects on blood metabolites and proteins remain to be elucidated. Similarly, it remains elusive whether spermidine acts exclusively on leukocytes to suppress chronic low-grade inflammation, and to what degree other organs may explain the increased bioavailability of arginine upon spermidine supplementation.

One strong argument in favor of the exploration of spermidine as a CRM in clinical trials is its low toxicity yet strong efficacy. Spermidine is an abundant natural polyamine contained in all organisms from bacteria to men and is naturally present in reasonable but varying amounts in human diets. Nevertheless, based on preclinical results, possible contraindications of spermidine administration such as advanced cancer and renal failure have to be defined. Last, it may be interesting to explore the development of artificial spermidine analogs with increased potency or ameliorated pharmacokinetic characteristics.

Schematic outline of the mechanisms of spermidine-mediated health effects.

The natural polyamine spermidine has prominent cardioprotective and neuroprotective effects, ameliorates aging-associated metabolic decline, and stimulates anticancer immunosurveillance in animal models. Autophagy is required for several of these health-promoting effects of spermidine. Spermidine also suppresses proinflammatory cytokines and improves the bioavailability of arginine required for NO biosynthesis. It remains an open question whether all these effects depend on the autophagy-stimulatory properties of spermidine.

Abstract

Interventions that delay aging and protect from age-associated disease are slowly approaching clinical implementation. Such interventions include caloric restriction mimetics, which are defined as agents that mimic the beneficial effects of dietary restriction while limiting its detrimental effects. One such agent, the natural polyamine spermidine, has prominent cardioprotective and neuroprotective effects and stimulates anticancer immunosurveillance in rodent models. Moreover, dietary polyamine uptake correlates with reduced cardiovascular and cancer-related mortality in human epidemiological studies. Spermidine preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence. Mechanistically, it shares the molecular pathways engaged by other caloric restriction mimetics: It induces protein deacetylation and depends on functional autophagy. Because spermidine is already present in daily human nutrition, clinical trials aiming at increasing the uptake of this polyamine appear feasible.

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