The Molecular Role of Polyamines in Age-Related Diseases: An Update

Abstract

Polyamines (Pas) are short molecules that exhibit two or three amine groups that are positively charged at a physiological pH. These small molecules are present in high concentrations in a wide variety of organisms and tissues, suggesting that they play an important role in cellular physiology. Polyamines include spermine, spermidine, and putrescine, which play important roles in age-related diseases that have not been completely elucidated. Aging is a natural process, defined as the time-related deterioration of the physiological functions; it is considered a risk factor for degenerative diseases such as cardiovascular, neurodegenerative, and musculoskeletal diseases; arthritis; and even cancer. In this review, we provide a new perspective on the participation of Pas in the cellular and molecular processes related to age-related diseases, focusing our attention on important degenerative diseases such as Alzheimerߣs disease, Parkinsonߣs disease, osteoarthritis, sarcopenia, and osteoporosis. This new perspective leads us to propose that Pas function as novel biomarkers for age-related diseases, with the main purpose of achieving new molecular alternatives for healthier aging.

Keywords: age-related diseases; aging; aging biomarkers; polyamines; putrescine; spermidine; spermine.

Figure 1

PA transport and metabolism. GPC1 transports spermine, putrescine is exported by the transporter SLC3A2, and spermine and spermidine are transported through OCT–1–3. In the first stage of PA synthesis, ornithine and agmatine are synthetized from arginine catalyzed by arginase and ADC, respectively. Agmatine can be transformed into putrescine and urea by agmatinase. Ornithine is then decarboxylated by ODC to synthetize putrescine and urea. Subsequently, putrescine is converted into spermidine and spermidine is converted into spermine by the action of spermidine synthetase and spermine synthetase, respectively. Spermidine is cleaved and transferred by DHS to eIF5A-Lys to catalyze the interconversion of deoxyhypusine, which is subsequently hydroxylated by DOHH to produce hypusine. In a second stage, dcAdoMet suffers a decarboxylation catalyzed by S–adenosine methionine decarboxylase (pyruvoyl), producing S–adenosine methionine–3–aminopropyl methyl sulfonate. The catabolism pathway of PA successively converts spermine into spermidine and spermidine into putrescine through the acetylated forms of PA (N–acetylspermine and N–acetylspermidine) catalyzed by SSAT and PAO. The degradation of PA leads to the production of highly toxic intermediaries such as aldehydes, peroxides, and ammonia. In particular, aldehydes are extremely reactive and degrade spontaneously, producing acrolein, a highly toxic compound.

Figure 2

Alterations of polyamine concentration in various age-related diseases. (A) Alzheimer’s disease: Predominantly increased polyamines are observed in the brain: SPM, SPD, and PUT increase in the frontal lobe (navy blue); SPM and SPD increase in the parietal lobe (light blue); SPD increases in the temporal lobe (green); and SPM increases while SPD decreases in the hippocampus of mice. In plasma, there is an increase in SPD and a decrease in its acetylated form, N-Ac-SPD. Glial cells show increases in SPD and SPM. (B) Parkinson’s disease: Acetylated forms of SPD, SPM, and SPD exhibit higher concentrations, along with an increase in SPD and a decrease in SPM in plasma. There is an increase in SPD and decreases in SPM and PUT in blood. PUT increases and SPD decreases in cerebrospinal fluid. Glial cells exhibit increases in SPD and SPM. (C) Osteoarthritis: PUT decreases in plasma, and SPM decreases at the knee. (D) Sarcopenia: SPM and SPD decrease in the muscle, while there is an increase in SPD and a decrease in SPM in blood. (E) Osteoporosis: There are decreases in SPD and PUT in osteoporotic bones. Labels indicate putrescine (PUT), spermidine (SPD), spermine (SPM), and their acetylated versions (Ac) either at the amino terminus (N-) or di-acetylation (Di). A higher concentration is indicated by a red arrow, while a lower concentration is denoted by a blue arrow, compared to healthy individuals. * Refers to studies using murine models.