Reviewing the Complexity of Immunosenescence
The immune system becomes more inflammatory and less competent with advancing age, undergoing sweeping changes in immune cell characteristics and relative population sizes. The cells, structures, and processes that produce immune cells similarly undergo significant changes. Taken together, this is called immunosenescence, though many researchers choose to break out the inflammatory component of dysfunction into its own category, calling it inflammaging. One of the most important goals for the research community is to find ways to improve immune function in older people.
Evidently, the decline of the immune system is an important aspect of aging. It produces many directly, obviously harmful consequences. The inability to defend against infectious disease leads to a tremendous death toll in older individuals, largely resulting from common infectious agents such as influenza, diseases that younger people can shrug off. Similarly, the ability to clear precancerous and senescent cells is also much reduced, driving the increased risk of cancer on the one hand, and the growing number of lingering senescent cells on the other. There are many more subtle issues, more poorly researched, however, in which aged immune cells play a harmful role, contributing to age-related disease and dysfunction in specific organs.
Immunosenescence: molecular mechanisms and diseases
Immunosenescence is a complex process that involves organ reorganization and numerous regulatory processes at the cellular level. As a result, immune system function decreases, leading to an inadequate response to infections or vaccines in elderly individuals. Although the full extent of the biological changes is unknown, several characteristic changes are typically observed such as thymic involution, hematopoietic stem cell (HSC) dysfunctions, disrupted naïve/memory ratio in T cells and B cells, inflammaging, accumulation of senescent cells, impaired new antigen response, mitochondrial dysfunction, genomic instability, and stress responses. Identifying hallmarks and characteristics associated with immunosenescence is crucial for exploring its impact and significance, particularly in age-related diseases.
Thymic involution plays a vital role in the imbalance of immune cell proportions, particularly for T cells. Thymic tissue can be divided into epithelial tissue and nonepithelial perivascular space without thymopoiesis. As the thymus atrophies, the epithelial spaces gradually disappear, and the perivascular space gradually fills the elderly thymus, leading to a decrease in naïve T cells, an increase in peripheral late-differentiated memory T cells, and diminished migration of naïve T cells to the periphery. According to the latest studies, thymic rejuvenation does not restore diversity, and we agree that thymic degeneration does not perfectly explain the decline in T-cell receptor (TCR) diversity in humans.
One of the hallmarks of immunosenescence is "inflammaging," which refers to a systemic state of chronic low-grade inflammation characterized by upregulated blood inflammatory markers and is considered the central pillar of aging. The accumulation of damaged macromolecules is responsible for inflammaging, and endogenous host-derived cell debris is the source of chronic tissue damage. Cellular senescence is central to the inflammaging process. Senescent cells exhibit a distinctive senescence-associated secretory phenotype (SASP), leading to the inflammaging phenotype. Cellular senescence has been hotly debated as a driver of immunosenescence.
As the immune system ages, metabolism undergoes changes that involve increased glycolysis, mitochondrial dysfunction, and reactive oxygen species (ROS). These features of immunosenescence are strongly related to high morbidity and mortality from age-associated diseases such as cardiovascular diseases, neurodegenerative diseases, autoimmune diseases, metabolic diseases, and cancers in older patients. As the incidence of these disorders exponentially increases later in life, common cellular and molecular mechanisms likely contribute to their development. In this context, it is crucial to examine the molecular mechanisms, altered immune cell pool, and regulatory signaling impact on immunosenescence and age-related diseases.
Moth viruses (as gene delivery vectors) can be targeted to specific tissues using magnetic fields. These could be used to express FOX1N in the thymus. It could be worth the SENS RF or LEV Foundation funding someone to try this out:
Moths and magnets could save lives
"The researchers use the magnetic nanoparticles to activate BV and deliver gene-editing payloads only where they're needed. To do this, they take advantage of an immune-system protein called C3 that normally inactivates baculoviruses.
"If we combine BV with magnetic nanoparticles, we can overcome this deactivation by applying the magnetic field," Bao said. "The beauty is that when we deliver it, gene editing occurs only at the tissue, or the part of the tissue, where we apply the magnetic field."
Application of the magnetic field allows BV transduction, the payload-delivery process that introduces gene-editing cargo into the target cell. The payload is also DNA, which encodes both a reporter gene and the CRISPR/Cas9 system.
In tests, the BV was loaded with green fluorescent proteins or firefly luciferase. Cells with the protein glowed brightly under a microscope, and experiments showed the magnets were highly effective at targeted delivery of BV cargoes in both cell cultures and lab animals.
Bao noted his and other labs are working on the delivery of CRISPR/Cas9 with adeno-associated viruses (AAV), but he said BV's capacity for therapeutic cargo is roughly eight times larger. "However, it is necessary to make BV transduction into target cells more efficient," he said."