▎ WuXi AppTec content team editor
Ageing and aging are issues that each of us has to face. With the aging of the population, the research and development of interventions and therapies to delay or even reverse aging is also becoming a hot research area.
Recently, eBioMedicine, a journal of The Lancet-Discovery Science, published an important advance in anti-aging therapies. The research team at the top institution Mayo Clinic has demonstrated through animal and human studies that the combination of anti-aging drugs dasatinib + quercetin (the "D+Q" regimen) can enhance a key protective protein in the body, thus helping to protect the elderly from aging and a range of diseases. Moreover, for this key protein, the study also opens up an innovative and clinically applicable pathway for the development of small molecules with oral activity.
Screenshot source: eBioMedicine
Age Protection Protein
The study focused on anti-aging targets is a protein called α-Klotho. α-Klotho is an age-protecting protein that acts as an antiphysiological stressor and protects against oxidative damage, hypoxia, and cytotoxic drug damage, thereby attenuating or mitigating harmful changes brought about by aging and disease.
However, as we age, levels of α-Klotho protein gradually decrease, and senescent cells (also known as "zombie" cells) accumulate. This phenomenon is particularly pronounced in patients with a variety of diseases, including Alzheimer's disease, diabetes, and kidney disease.
Animal studies have shown that reducing α-Klotho in mice shortens their lifespan, while increasing α-Klotho by inserting genes increases the lifespan of mice by 30%.
Finding ways to increase the α-Klotho in humans has naturally become one of the important research goals. However, because α-Klotho must be given intravenously and cannot be administered orally and is unstable, direct supplementation with α-Klotho is difficult.
This time, the research team took a different approach. Since senescent cell accumulation is associated with multiple organ tissue dysfunction and a variety of age-related diseases, the research team speculates that α-Klotho and cellular senescence are equally interrelated and have opposite effects, and try to increase the α-Klotho protective protein in the body through an ongoing oral drug that can remove senescent cells.
Removing senescent cells is feasible
The team first demonstrated that senescent cells do reduce levels of α-Klotho in three types of human cells: including umbilical vein endothelial cells, kidney cells, and brain cells.
The research team cultured three different types of non-senescent human primary cells with senescent or non-senescent cells and analyzed α-Klotho expression. It was found that exposure to senescent cells reduced the expression of α-Klotho in a variety of non-senescent human cells. Antibodies to neutralize aging-related secretion of phenotypic (SASP) factors, activator A, and interleukin (IL)-1α partially prevent the reduction of α-Klotho.
Next, the research team further verified this through animal experiments:
Transplanting senescent cells into young mice reduced the α of the mouse kidneys and brains with the Klotho protein.
Conversely, for mice with increased burden on senescent cells (including natural aging, diet-induced obesity, or mice transplanted with senescent cells), selective removal of senescent cells by genes or drugs increased α-Klotho protein in the kidneys, urine, and brain.
Image credit: 123RF
Human studies are beginning to emerge
Finally, the research team measured improvements in urine α-Klotho protein levels in patients with idiopathic pulmonary fibrosis (IPF) on the dasatinib + quercetin ("D+Q" protocol).
IPF is a typical cellular aging-related disorder that can lead to weakness, severe dyspnea, and death. The "D+Q" scheme is a "Senolytic therapy" that directly targets senescent cells. Among the current strategies to eliminate senescent cells, "Senolytic therapy" is a category of high hopes. A small clinical study previously led by Miaoyou Medical International has shown that D+Q treatment has brought clinically significant improvements in patients' physical function, including walking distance, walking speed, seat standing ability, and simple physical fitness assessment scores.
The results of this analysis also showed that the levels of α-Klotho in the urine of these IPF patients after oral administration of D+Q did increase, and that SASP factor (senescent cell-related) in the urine was negatively correlated with α-Klotho levels. This also suggests that urine α-Kloth may be used as a marker in anti-aging clinical trials.
▲Aging and obesity will lead to a decrease in protective protein α-Klotho, while the removal of senescent cells can increase the α-Klotho (Image source: Reference[1])
brief summary
The paper concludes that both α-Klotho and cellular senescence are associated with the onset and progression of age-related diseases, which are negatively correlated and causally linked. Targeting the elimination of senescent cells increases the level of the aging protective factor α-Klotho, potentially amplifying the beneficial effects of anti-aging drugs.
"Our study shows that taking small molecules by mouth can increase the beneficial protein α Klotho and enhance the effects of anti-aging drugs." Study corresponding author Dr James L. Kirkland, International Centre for Aging at Myoyo Healthcare, said.
"We were the first to find that senescent cells have a potential effect on the brain's α- Klotho, which may open up another avenue for studying the effects of peripheral senescent cells on brain aging." Dr. Yi Zhu, lead author of the study, a physiologist and biomedical engineer at Myoyo Medical International, added.