Fatty Acid Metabolism and Age-Related Heart Failure
Researchers here propose that alterations in fatty acid metabolism in aged heart tissue make up one of the contributing factors to the age-related loss of function in the heart, a process that eventually leads to heart failure and death. As a mechanism this is is situated somewhere in the middle of the chain of cause and consequence that starts with molecular damage caused by the normal operation of metabolism, a sort of biological wear and tear, then passes through a complex series of reactions to that damage, some helpful and some harmful, and finally leads to functional failure in organs as the network of damage and consequences becomes too much.
Age-related cardiac dysfunction is a major factor in heart failure. The elderly accounts for at least 80% of patients with ischemic heart disease, 75% of patients with congestive heart failure, and 70% of patients with atrial fibrillation. Heart failure with either lower or preserved ejection fraction is common for hospitalized patients with cardiac abnormalities. Cardiac aging, which is evident in both humans and mice, plays an important role for both types of heart failure. Several components of cardiac function, including energetic homeostasis, adrenergic signaling, and mitochondrial dysfunction, can be compromised during aging. Balanced cardiac lipid metabolism is critical for normal function of the heart. Any deviation toward either increased or reduced fatty acid metabolism may be detrimental for cardiac function, primarily depending on the type of pathophysiological challenge. Aging-related cardiomyopathy has been associated with downregulation of peroxisome proliferator-activated receptor (PPAR)-α, which is a central regulator of cardiac fatty acid metabolism and cardiac lipid accumulation. Thus, impairment of fatty acid metabolism may at least partially account for the aggravation of cardiac function that occurs with aging.
The heart normally consumes a large amount of ATP in order to pump more than 7,000 liters of blood on a daily basis. For the production of ATP that is needed for this massive amount of work, the heart oxidizes fatty acids, glucose, lactate, ketone bodies, and amino acids as energy-providing substrates. Fatty acid oxidation (FAO) is a major component of the energy production process as it accounts for the generation of approximately 70% of cardiac ATP. FA utilization in healthy hearts is a complex process that includes several steps, including: FA uptake, transfer of fatty acids into the mitochondria, and oxidative phosphorylation for ATP production. The flawless transfer of fatty acids from cellular uptake to mitochondrial oxidation prevents accumulation of excess lipids. A study in humans showed that aging decreases myocardial FA utilization and FAO without any difference in myocardial glucose utilization. Several types of cardiac dysfunction are associated with impaired FAO, which frequently leads to lipid accumulation characterized as cardiac lipotoxicity.
Although cardiac toxic lipids have been associated with cardiac dysfunction, it has not been studied thoroughly whether they mediate aging-related cardiomyopathy, as well as what lipid-driven signaling mechanisms may be involved. Various studies have established a correlation between cardiac lipid accumulation and aging in humans and animal models. Several proteins of the energy production machinery that mediates processing of FAs and ATP production are regulated at the transcriptional level by PPARα. The importance of PPARα inhibition in accelerating cardiac aging was demonstrated in 20-month-old rats that were treated with the lipid lowering drug atorvastatin, which increases PPARα expression. The treatment with atorvastatin reduced cardiac hypertrophy, collagen deposition, oxidative stress, expression of inflammatory cytokines, and the aging marker β-galactosidase. Although reduced cardiac PPARα expression has been associated with aging-related cardiomyopathy, the underlying mechanisms that mediate the beneficial effect of PPARα have not been fully elucidated.
In summary, cardiac FAO is important for lipid metabolism homeostasis and normal cardiac function. Inhibition of FAO leads to increased cardiac lipid content, which is often accompanied by increased levels of toxic lipids. These lipids compromise cardiac function via β-adrenergic receptor desensitization, which is driven by activation of the protein kinase C signaling pathway. Aging-related cardiomyopathy is associated with reduced cardiac levels of PPARα, a master regulator of cardiac FAO, as well as with inhibition of β-adrenergic receptor signaling and mitochondrial dysfunction. These components of cardiac lipotoxicity that are also involved in cardiac aging indicate therapeutic targets that may alleviate age-related cardiomyopathy.
I hope it will be possible in the future to pin down the underlying causes of each and every disease associated with aging. For example, this paper states that PPARalpha is downregulated in the elderly but that is not the primary cause of the altered fatty acid metabolism because there has to be some reason why it is downregulated. It must be a complicated interaction between the initial damage (seven forms of it of you are right) and metabolism which then alters gene expression. The altered gene expression has further consequences in a chain of reactions that leads to the phenotype of disease. It is known that senescent cells heavily influence their local environment and eventually the effects become systemic. But why do senescent cells actually increase with age? Is it the decline of the immune system including impaired function of the Natural Killer cells that are supposed to clear them from the body or is it a very slow but steady accumulation because of mitochondrial gene mutations spreading? Is it both?What is the role of aging stem cells in all this? I'm still trying to so understand the hierarchy and interconnection between cause and consequence.
The way Judith Campisi explained it on the recent conference it's a pool of death resistant senescent cells that accumulates. Not all senescent cells are death resistant, but the ones that accumulate are. There is a good chance the reason for them being death resistant is mutagenesis, after all it seems most cancers start from precisely these death resistant senescent cells.