Could a so-called longevity gene help restore heart health?
- Studies have shown that the longevity-associated variant (LAV) of the BPIFB4 gene is associated with a longer lifespan in humans and has protective effects in rodent models of cardiovascular disease.
- A new study shows that LAV-BPIFB4 may exert its cardioprotective effects by promoting the formation of new blood vessels and reducing the number of blood vessel cells that have become senescent and stopped multiplying.
- The study indicates that inducing the expression of LAV-BPIFB4 in aged mice improved cardiac function and regulation of blood flow to the heart.
- These findings highlight the therapeutic potential of LAV-BPIFB4 for attenuating the adverse effects of aging on cardiovascular function.
A recent study published in Cardiovascular Research suggests that LAV-BPIFB4, a gene variant that previous research ha shown to be highly expressed by individuals with an exceptionally long lifespan, could also protect cardiac and vascular function in old age.
In the new study, inducing the expression of LAV-BPIFB4 in aged mice led to improvements in cardiac function that, translated to the human context, would be equivalent to a reduction in the heart’s biological age by 10 years.
Study author Dr. Paolo Madeddu, professor of experimental cardiovascular medicine at Bristol University in the United Kingdom, told Medical News Today:
“It is known that centenarians can pass their healthy genes to their offspring. This study demonstrates that it is also possible to make human cardiac cells younger and older mice hearts by transferring a gene expressed by centenarians. We also demonstrate that the benefit is related to the ability of the gene to reprogram cardiac cells to become more resistant to stress and build up the machinery (ribosomes) that make proteins.”
Aging and cardiovascular disease
The heart has four chambers — two upper chambers called atria that receive blood from the body, and two lower chambers called the ventricles that pump blood to the body.
The right atrium receives deoxygenated blood from the body, and the right ventricle pumps the deoxygenated blood to the lungs. The left atrium receives oxygen-rich blood from the lungs, which is then pumped into the left ventricle.
Upon the contraction of the left ventricle, oxygenated blood is transported to the rest of the body. The functioning of the heart itself requires oxygen and nutrients that are supplied by the coronary arteries.
Aging is associated with an increase in the risk of cardiovascular conditions, including heart attack, heart failure, and coronary artery disease. These cardiovascular conditions are caused by alterations in the structure and function of the heart and blood vessels, including the coronary arteries.
These changes include an increase in the thickness and stiffness of the walls of the coronary arteries and the left ventricle. The thickening of the left ventricle, known as left ventricular hypertrophy, can result in complications such as heart failure, which is the inability of the heart to pump sufficient quantities of blood to the body.
Another change associated with aging involves the dysfunction of endothelial cells, which form the inner lining of blood vessels and the heart.
Endothelial cells regulate the blood flow as well as the exchange of fluids and molecules between the blood and the tissue. The dysfunction of endothelial cells results in the narrowing of arteries and can increase the risk of cardiovascular diseases.
Endothelial cells also play an important role in angiogenesis, the process of formation of new blood vessels from preexisting ones. Endothelial dysfunction during aging is also associated with the reduction in the density of capillaries, the small blood vessels that transport oxygen and nutrients to tissues.
Thus, endothelial cell dysfunction can lead to a reduction in the blood supply to the heart muscle by coronary arteries, thus increasing the risk of a heart attack or myocardial infarction.
Pericytes or perivascular cells are cells that are embedded at intervals along the walls of capillaries and wrap around endothelial cells. Pericytes interact with endothelial cells to play an important role in the formation of new blood vessels and the maintenance of blood vessels.
Whilst the evidence is mixed, some studies have suggested that aging is associated with a decline in the coverage of endothelial cells by pericytes, resulting in increased permeability of blood vessels. Thus, in addition to endothelial cells, impaired pericyte function may contribute to cardiovascular diseases.
Effects of LAV-BPIFB4 on vascular cells
In the present study, the researchers first examined the potential mechanisms underlying the protective effects of LAV-BPIFB4 in cardiovascular conditions.
They examined the differences in the hearts obtained from elderly ischemic heart failure patients undergoing heart transplantation surgery and those from individuals who died due to reasons other than cardiovascular complications.
The hearts obtained from ischemic heart failure patients showed lower expression levels of BPIFB4 in the cardiomyocytes and endothelial cells than individuals with healthy hearts. The hearts of ischemic failure patients also had lower capillary density than healthy hearts.
Moreover, there was a reduction in the density of pericytes and lower coverage of blood vessels by pericytes in hearts obtained from ischemic heart failure patients.
Among ischemic heart failure patients, individuals who expressed the LAV variant of BPIFB4 on both chromosomes showed a higher density of pericytes and greater coverage of capillaries by pericytes than those who carried a single or no copies of the LAV-BPIFB4 gene.
However, these groups did not differ in capillary density, suggesting that LAV-BPIFB4 preserves the coverage of capillaries by pericytes without influencing the capillary density.
The pericytes isolated from the hearts of ischemic heart failure patients showed greater expression of markers of oxidative stress and cellular senescence. Senescence refers to the permanent arrest of cell growth and is observed in response to cellular stress and aging.
The researchers found that the addition of LAV-BPIFB4, but not other forms of BPIFB4, to cultured pericytes isolated from the heart of ischemic heart failure patients reduced the expression of senescence and oxidative stress markers.
Pericytes from the hearts of ischemic failure patients also showed a downregulation of the protein synthesis machinery, which is associated with cellular aging. The addition of LAV-BPIFB4 led to the upregulation of the protein synthesis machinery in the pericytes isolated from the hearts of ischemic heart failure patients.
Previous studies have shown that endothelial cell senescence is associated with impaired angiogenesis. In subsequent experiments conducted using endothelial cell cultures, LAV-BPIFB4 enhanced the ability of senescent endothelial cells to form new blood vessels to a greater extent than other BPIFB4 variants.
LAV-BPIFB4 also increased the secretion of molecules that promote angiogenesis by pericytes isolated from the hearts of patients with ischemic heart failure.
Preincubation of pericytes from ischemic heart failure patients with LAV-BPIFB4 also enhanced the ability of these pericytes to support the formation of new blood vessels by senescent endothelial cells.
These results suggest that LAV-BPIFB4 could directly enhance the ability of senescent endothelial cells to form new blood vessels as well as indirectly by promoting the secretion of molecules by pericytes that act on endothelial cells. In other words, the LAV-BPIFB4 gene could help restore deficits in the function of aged vascular cells.
Impact on aged mice
In their previous work, the study’s authors had shown that delivery of LAV-BPIFB4 using a viral vector, which involves the use of a harmless virus carrying the gene of interest, could enhance the expression of the protein in the heart of a mouse model of diabetes.
In the present study, the authors delivered either LAV-BPIFB-4 or a different BPIFB4 variant to middle-aged and old mice using a viral vector.
The aged mice showed a decline in cardiac function at baseline compared with middle-aged mice. The delivery of LAV-BPIFB4 to middle-aged and old mice was associated with an improvement in the function of the left ventricle.
Aging is also associated with a decline in the ability of the blood flow from coronary arteries to meet the demands of the heart muscle in response to exercise or stress. This is described in terms of coronary flow reserve, which is a ratio of the maximum increase in coronary blood flow in response to stress to the coronary blood flow at baseline.
To simulate the heart’s response to stress, the researchers used dobutamine, a drug that mimics the effects of beta-adrenaline released during stress.
Treatment with LAV-BPIFB4 increased coronary blood flow at baseline and in response to dobutamine in both middle-aged and older rats. This suggests that LAV-BPIFB4 could have helped restore deficits in coronary blood flow in response to stress.
These improvements in cardiac function after LAV-BPIFB4 treatment were accompanied by an increase in blood vessel and pericyte density and pericyte coverage in the hearts of middle-aged and older mice while reducing the number of senescent cells.
In addition to cardiomyocytes, the cardiac tissue also consists of fibroblasts, nerve endings, and immune cells. These cells are embedded in an extracellular matrix secreted by fibroblasts. The extracellular matrix consists of collagen and other proteins and plays a pivotal role in maintaining the structure and function of the heart.
Conditions such as aging and heart failure are associated with cardiac fibrosis involving the excess deposition of collagen in the extracellular matrix.
Cardiac fibrosis leads to the stiffness of the cardiac walls and a decline in cardiac function. In the present study, LAV-BPIFB4 treatment reduced the levels of myocardial fibrosis in the hearts of aged mice.
These results suggest that LAV-BPIFB4 could attenuate the effects of aging on cardiac function and structure.
Dr. Yu-Ming Ni, a cardiologist specializing in noninvasive cardiology at MemorialCare Heart and Vascular Institute at Orange Coast Medical Center in Fountain Valley, CA, explained that “this research study suggests that [the] LAV-BPIFB4 gene variant associates with better heart health and longevity, and improved heart health when used as a treatment in heart cells.”
“While these findings are promising, this finding will need to be tested in a research study involving people before it can be considered for improvement of heart health and longevity,” he nonetheless cautioned.