Delivering AUF1 to Decrease Vascular Inflammation
Vascular inflammation is of note in aging because it speeds up the various processes that cause stiffening and dysfunction in blood vessels, which in turn leads to the spectrum of debilitating and fatal cardiovascular diseases that are collectively responsible for a sizable fraction of human mortality. Senescent cells appear to be a major cause of this rising inflammation, and targeted destruction of these harmful cells is proving beneficial in animal studies, but most scientists interested in blood vessel inflammation are instead looking for ways to interfere in inflammatory signaling. Adjusting cellular reactions to the root causes of aging is far more popular as a strategy than repairing those root causes, such as by removing senescent cells, sad to say. Similarly, slowing the progression of root causes is far more popular than reversing or removing them. Until this changes progress towards increased healthy longevity will remain frustratingly slow.
The research noted here is an example of the type. AUF1 has been found to be involved in muscle stem cell activity, among other items, but more pertinently also appears to control inflammatory signaling. Mice lacking AUF1 suffer accelerated aging, while the presence of more AUF1 acts to dampen inflammation. Thus the authors of this paper have packaged a therapy that delivers AUF1 to vascular tissues, and tested it in mice in an effort to block some of the secondary inflammatory consequences that arise from the root cause cell and tissue damage of aging.
Currently, aging and anti-aging research has become a focus worldwide. Living standards and quality of life will continue to improve in the 21st century as scientific countermeasures to aging progress. With increasing age and cell degeneration, vascular endothelial cells (VEC) renew very slowly and show manifestations of aging. Long-term stimulation by pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), leads to chronic and low-grade microinflammation of VECs, which leads to age-related degenerative diseases. Many studies have shown close correlations between inflammation and DNA damage and between cell senescence and aging. Animal experiments have found that inhibition of VEC inflammation could delay aging and prolong life, thus it is imperative that we further investigate inhibition of VEC senescence.
Studies have shown that the AU-rich region connecting factor 1 (AUF1) gene controls the inflammatory response and maintains chromosome integrity by activating telomerase to repair the ends of chromosomes, thus AUF1 reduces inflammation and prevents rapid aging. By delivering AUF1 to VECs, we may be able to weaken the inflammatory cytokine response. Platelet endothelial cell adhesion molecule-1, which is also called cluster of differentiation 31 (CD31), is a member of the immunoglobulin superfamily and is expressed on endothelial cells, platelets, macrophages, and neutrophils and is involved in inflammatory angiogenesis. Inflammation, cell adhesion, and migration of endothelial cells play important roles in inflammatory angiogenesis, thus it is feasible to target CD31 to modulate VECs.
By inhibiting VEC inflammation, aging may be delayed and life may be prolonged. However, there is no targeted therapy for the aging of vascular endothelial cells. To enhance the effects of anti-aging treatments, we constructed a drug delivery system using liposomes conjugated with anti-CD31 monoclonal antibody (CD31-PILs) because anti-CD31 monoclonal antibody targets VECS. This CD31-PILs delivery system was able to encapsulate the AUF1 plasmid and to deliver it to VECs. A decline in cell proliferation ability is one of the biological signs of aging, and cell cycle changes can reflect the ability of a cell to proliferate. Analysis of cell cycle distributions showed that after treatment with CD31-PILs-AUF1, the percentages of cells in division phases significantly increased, while the percentages reduced non-division phases. These data are consistent with previous reports that AUF1 plays roles in anti-aging and in maintaining cell proliferation, thus, delivery of the AUF1 plasmid may play a role in anti-aging.
Our findings are consistent with earlier work showing increased IL-6 expression in old rats compared with young rats and after anti-inflammatory treatment, inflammation related factors are reduced and symptoms of aging can be improved. Whether the effects of these cytokines are mediated through the generation of intracellular reactive oxygen species, or through another defined cell-signaling mechanism, is under further study.
To verify the effect of CD31-PILs-AUF1 in vivo, we developed an aging mouse model using D-galactose. The result show D-galactose accelerates aging in rodents by inducing oxidative stress by increasing the malondialdehyde (MDA) level and reducing superoxide dismutase (SOD) activity. This is consistent with previous reports, indicating the success of the aging mouse model. MDA content decreased and the SOD content increased in mice treated with CD31-PILs-AUF1 indicating that CD31-PILs-AUF1 may delay the senescence induced by D-galactose. In conclusion, we have developed an effective PILs strategy to deliver the AUF1 plasmid to a specific target, and this system may be useful for the development of new anti-aging drugs.