Aging progressively leads to dysfunction of the immune system due to the loss of the genomic integrity of its cells and promotes an increased risk of diseases including cancers. Targeting aging rather than its consequences would, according to a study, be a more advantageous strategy for reducing morbidity among the elderly. Researchers have studied the mechanisms that weaken DNA and observed the effects of lamin A/C protein deficiency on lung tumors.
Cancer and aging are closely linked processes and yet the mechanisms at the heart of this relationship remain relatively unknown. By studying immune cells in the lung, researchers from the Institut Curie and Inserm have provided new knowledge on the subject. They reveal in particular that targeting ruptures in the nuclear envelope of these cells would represent a new opportunity for therapeutic intervention in age-related diseases, notably cancer, thus improving the quality of life of elderly people in the long term. Funded by the ARC Foundation, this work has just been published in the journal Nature Aging.
Age is one of the main risk factorsrisk factors for the development of many pathologiespathologies such as viral or bacterial infections, neurodegenerative diseasesneurodegenerative diseases but also cancers. The economic and societal issues linked to the overall aging of the population constitute a major challenge. Furthermore, the notion of “healthy aging” increasingly suggests that targeting aging rather than its consequences is a much better strategy for reducing the risk of aging. morbiditymorbidity of the elderly population.
In France, more than two thirds of new cancers diagnosed occur in people aged over 65. The appearance of cancerscancers with age is explained in particular by the accumulation of genetic alterations during life, of repair mechanisms of theDNADNA less effective, but also by a immune systemimmune system aging, with diminished protective functions (immunsenescence). What are the mechanisms that govern this phenomenon? How can we develop new strategies to counteract immunosenescence?
Deformations of the nucleus of the immune cell weaken its DNA
These are the questions that scientists from Inserm and the Institut Curie tried to answer. Over time, DNA becomes fragile and one of the characteristic markers of cell aging is instability. genomicsgenomics. However, when they patrol the different tissues of the body, the cells of the immune system are sensitive to deformations which weaken their nucleus and promote DNA breaks. To maintain the structure of the nucleus and therefore theintegrityintegrity genomics, the cell relies on a dense network of proteinsproteins of which laminas are a part. Among them, lamin A/C is particularly studied because it undergoes alterations during aging. In addition, mutations at the level of embarrassedembarrassed which codes for this protein are known to be at the origin of syndromessyndromes early aging.
“ Repeated disruptions of the nuclear envelope lead to DNA damage. It is essential to fully understand the processes involved at this level because they promote not only the aging of the body but also the development of cancers. For example, breaks in the nucleus make the DNA “visible” by degradation proteins, triggering a response from the cell which will promote the development of metastasesmetastases », explains Dr Nicolas Manel, research director at Inserm and team leader at the Institut Curie.
What happens in the absence of the lamin A/C protein?
At the Institut Curie, the Innate Immunity team of Dr Nicolas Manel, research director at Inserm, therefore studied a new experimental model in which the cells of the immune system are deficient in lamin A/C. The researchers examined a population of lung macrophages — alveolar macrophages — that are highly dependent on lamin A/C for their survival. These alveolar macrophages have the role of constantly monitoring the lungs and they constitute one of the main routes of entry for many pathogenspathogens.
The researchers showed that in the absence of lamin A/C, alveolar macrophages show severe signs of nuclear fractures and DNA damage, leading to a drastic reduction in their numbers in the lungs. Furthermore, surviving alveolar macrophages exhibit many similar characteristics to aged alveolar macrophages and accumulate markers characteristic of aging.
The team also demonstrated that in the absence of lamin A/C in macrophages, the implantation and growth of lung tumors is much faster, favored by the dysfunction of aged macrophages. The loss of lamin A/C would therefore represent a mechanism of aging of alveolar macrophages and a study model of choice to understand how lung cancerslung cancers develop in older people.
“ Our results open up numerous perspectives for the study of the aging of the immune system caused by the breakdown of the nuclear envelope and the reduction in its effectiveness against infections and tumorstumorsin the lungs, but also in other organs », concludes Dr Nicolas Manel.
