Heart failure is one of the leading causes of disability, rehospitalisation and death in older people. Despite its major health impact, the mechanisms explaining why the ageing heart is more vulnerable to this disease are still not fully understood. A study led by the Cardiovascular Diseases group at the Vall d’Hebron Research Institute (VHIR) has identified a key cause that drives cardiac deterioration with ageing. The work was carried out in collaboration with the Cardiovascular Diseases and Epidemiology and Public Health areas of CIBER (CIBERCV and CIBERESP), the Spanish National Centre for Cardiovascular Research (CNIC) and Thomas Jefferson University in Philadelphia, and has been published in the journal Aging Cell.

From the accumulation of metabolic by-products to cardiac deterioration

To investigate what happens in the heart during ageing, the team studied animal models* that physiologically reach advanced ages, combined with cellular models simulating ageing. Using high-resolution microscopy techniques and large-scale proteomic analysis, they examined in detail the changes occurring inside the cells.

In this way, the researchers identified the key role of advanced glycation end products (AGEs) on mitochondria, the organelles responsible for generating energy within cells. AGEs are chemical compounds derived from metabolism and, as they accumulate in mitochondria, they cause these organelles to lose energy efficiency. This process triggers a chain reaction: the chemical damage also affects lysosomes, which are responsible for removing damaged cellular components, leading to a progressive disruption of the cellular recycling system and promoting the accumulation of waste within cells.

The persistence of this cellular stress causes some cardiomyocytes to enter a state of senescence, a transformation that allows them to survive but impairs their normal function. “Although these cells do not die, they undergo significant structural and functional changes and adopt a pro-inflammatory profile that spreads locally and contributes to cardiac deterioration”, explains Dr. Marisol Ruiz Meana, principal investigator of the Cardiovascular Diseases group at VHIR and CIBERCV.

Towards new therapeutic strategies

These findings open the door to new therapeutic approaches aimed at preventing or delaying age-related heart failure. In particular, targeting the mechanisms that drive AGE formation or restoring lysosomal digestive activity could be promising strategies.

“The identification of this mechanism allows us to better understand how ageing promotes the onset of heart failure and opens up new opportunities to develop therapies aimed at protecting the heart”, concludes Dr. Marisol Ruiz-Meana.

This study was funded by the Instituto de Salud Carlos III (ISCIII), an organisation under the Spanish Ministry of Science and Innovation.

*Institutional Statement on the use of research animals