Role of polyamines in aging: impact of spermidine consumption on neurodegeneration.

Age-dependent neurodegeneration is associated with both environmental factors and genetic mutations, determining a complex range of common denominators like genomic instability, loss of proteostasis, mitochondrial dysfunction, epigenetic alterations, altered cell signaling and impaired nutrient sensing [1]. Deregulation of the cellular mechanisms of defense uncharged of controlling and antagonizing the time-dependent accumulation of cellular damage can lead to accelerated aging and neurodegenerative disease. Age dependent memory impairment starts in midlife and worsens with advancing age, suggesting that the greatest driving factor is age itself [2]. The senescence-accelerated mouse prone 8 (SAMP8) strain is a spontaneous animal model of accelerated aging, and age dependent cognitive impairment. Polyamines have been found to be associated with aging: in several organisms, including yeast and humans, the levels of polyamines decrease with age [3]. Remarkably, restoring their levels have resulted to be beneficial. In this study we have simulated a spermidine-rich diet in SAMP8 and its control strain SAMR1, by supplementing 2mM spermidine ad libitum in drinking water, starting from 2 months of age. We analyzed the levels of different metabolites in blood, brain and small intestine of mice both in treated and control groups of both mice strains. In particular, we have focused on polyamines metabolism (putrescine, spermidine, spermine), NAD metabolism (nicotinate mononucleotide, NaMN, nicotinamide mononucleotide, NMN, nicotinate adenine dinucleotide, NaAD, nicotinamide adenine dinucleotide, NAD, nicotinamide, Nm) and ATP metabolism (ATP, ADP, AMP), in order to assess differences between treated and control groups and among the strains, and also to infer a possible interplay between spermidine administration and energetic metabolism. We also tested cognitive performance of SAMP8 and SAMR1 mice, by using Novel Object Recognition (NOR), a short-term memory test. The obtained results shown that spermidine treatment has the following effects on SAMP8 mice:  it favours putrescine increase in blood, brain and small intestine. The increase of putrescine is a mechanism normally adopted to counteract the effects of aging;  it decreases NaMN levels in blood and favours NAD synthesis in small intestine;  it determines the increase of ATP in blood and brain;  spermidine consumption has an impact in ameliorating cognitive performance of ten months old SAMP8 mice. References: [1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217. [2] Gupta,V.K., Pech, U., Bhukel, A., Fulterer, A., Ender, A., Mauermann, S.F., et al. (2016) Spermidine suppresses age-associated memory impairment by preventing adverse increase of presynaptic active zone size and release. PLoSBiol 14(9):e1002563. [3] Minois, N., Carmona-Gutierrez, D., & Madeo, F. (2011). Polyamines in aging and disease. Aging (Albany NY), 3(8), 716-732.