Spermidine Promotes Cardiovascular Health in Rodents
The dietary compound spermidine exhibited potent cardioprotective properties in a recent study conducted in rodent models of physiological cardiac aging and high salt–induced congestive heart failure.
The Nature Medicine study builds on previous research indicating that spermidine extends longevity and health span in yeast, flies, and worms by inducing autophagy, which is thought to help minimize the functional decline of aging cardiomyocytes by degrading and recycling cellular components.
A team led by investigators in Austria reports that when middle-aged mice were given drinking water supplemented with spermidine, which is synthesized by the body but is also present in foods such as aged cheese, legumes, and whole grains, the animals’ median lifespan was prolonged by ≈10%, with no effects on body weight and lean or fat mass composition.
Structural and functional cardiac tests revealed that the spermidine-fed mice exhibited improvements in diastolic function and cardiomyocyte composition. Such benefits were not seen in spermidine-fed mice with a cardiomyocyte-specific autophagy defect, however.
In Dahl salt-sensitive rats fed a high-salt diet, which represents a clinically relevant animal model of hypertension-induced hypertrophy, diastolic dysfunction, and heart failure, spermidine supplementation reduced blood pressure and delayed progression to heart failure. It also delayed the appearance of several signs of hypertensive renal injury in the animals.
Finally, when the scientists assessed dietary spermidine intake through food questionnaires in a population-based cohort, they found that intake was inversely associated with risks of fatal heart failure (with an ≈40% reduced risk for high versus low spermidine intake), clinically overt heart failure, and a composite of acute coronary artery disease, stroke, and death attributable to vascular disease. Spermidine intake also showed an inverse association with plasma levels of soluble N-terminal pro-B-type natriuretic peptide, a biomarker for heart failure. In addition, systolic and diastolic blood pressures were significantly lower in individuals with high intake of spermidine versus those with low intake.
The findings suggest that prospective clinical trials to test the therapeutic potential of dietary spermidine in humans are warranted.
Cellular Reprogramming May Reverse Hallmarks of Aging
New research indicates that reprogramming cells to a pluripotent state can reverse cellular aging in live animals, an advance that goes well beyond what has been shown in vitro. In addition to the effects on individual cells, such reprogramming also reversed physiological signs of aging, such as declines in the regenerative capacity of tissues and organs during life.
The research is based on forced expression of the so-called Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc), which are known to reprogram cells through epigenetic alterations such as DNA methylation, posttranslational modifications of histones, and chromatin remodeling.
As reported in their Cell study, investigators in the United States and Spain first tested the effects of inducible expression of the Yamanaka factors in mice with a genetic mutation that leads to the accumulation of a truncated form of lamin A (called progerin), which is responsible for human Hutchinson-Gilford progeria syndrome, a progressive genetic disorder that causes children to age rapidly. Treatment ameliorated various hallmarks of aging, including the accumulation of DNA damage, cellular senescence, epigenetic dysregulation, and nuclear envelope defects. Furthermore, it dramatically increased lifespan in this mouse model.
In tests conducted on physiologically aged mice, short-term expression of the Yamanaka factors improved recovery from metabolic disease and muscle injury. Knowing that pancreatic β-cells lose their regenerative capacity during aging, investigators examined β-cell responses following pancreatic injury in older mice treated with and without the Yamanaka factors. Treatment promoted expansion of the beta cell population in the animals and increased their glucose tolerance. Similarly, intramuscular delivery of the Yamanaka factors led to the expansion of muscle stem cells in older mice and improved muscle regeneration following injury.
Such experiments demonstrate how cellular reprogramming may help prevent glucose imbalances and muscle mass loss, which could in turn protect against diabetes mellitus and functional decline as individuals age. Numerous other processes in the body that become compromised over time might also be preserved through such a strategy.
Hypoxia may hold the key to heart regeneration
Although research has indicated that the adult mammalian heart cannot regenerate following cardiomyocyte loss, under certain circumstances it appears capable of modest self-renewal. Armed with evidence that oxygen-dependent mitochondrial metabolism is a major driver of cell cycle arrest in cardiomyocytes, a team led by scientists at The University of Texas Southwestern Medical Center recently tested whether gradual decreases in inspired oxygen might stimulate cells to reenter the cycle.
In a Nature study, mice were exposed to a drop in the fraction of inspired oxygen by 1% per day from 20.9% to 7%, followed by exposure to 7% oxygen for an additional 2 weeks. The treatment inhibited oxidative metabolism, decreased reactive oxygen species production and oxidative DNA damage, and reactivated cardiomyocyte mitosis.
Also, exposure to hypoxia 1 week after myocardial infarction caused a robust regenerative response with decreased myocardial fibrosis and improved left ventricular systolic function.
The researchers note that it may be counterintuitive to use the lack of oxygen, which is the most common cause of cardiomyopathy, to regenerate the injured heart; however, short and gradual exposure to hypoxia may hold considerable promise. n
Circulation is available at http://circ.ahajournals.org.
- © 2017 American Heart Association, Inc.