Aging pathobiology and therapeutics最新文献

The hallmarks of aging have contributed immensely to the systematization of research on aging and have influenced the emergence of geroscience. The developments that led to the concepts of the hallmarks and geroscience were first marked by the proliferation of 'theories' of aging, mostly based on the experimental predilections of practitioners of aging research. Deeper consideration of the concepts of hallmarks of aging and geroscience leads to the quandary of whether a biological aging process exists beyond disease itself. To address this difficulty, a metric of biological age as opposed to calendar age is necessary. Several examples of biological age measured using similar assumptions, but different methods, exist. One of these, the frailty index was the first to successfully characterize aging in terms of loss of integrated function, and it is simpler than and superior to other constructs for measuring biological age. Though relatively simple in construction, the frailty index is rich conceptually, however, pointing to a network model of the aging organism. This network functions as a nonlinear complex system that is governed by stochastic thermodynamics, in which loss of integration leads to increasing entropy. Its structure transcends all levels of biological organization, such that its parts form hierarchies that are self-similar (fractal). The hallmarks of aging are simply nodes in the aging network, which can be found repetitively in various locations of the network. Stochastic thermodynamics implies that the aging system with higher entropy can exist in a multitude of possible microstates that are tantamount to high disorder with a high probability to assume a certain state. This explains the observed variability among aging individuals.

Background: Patients with Hutchinson-Gilford progeria syndrome (HGPS) show accelerated aging phenotypes and have shortened lifespan, with implications in physiological aging processes as well. While therapeutic approaches targeting the disease-causing abnormal protein, progerin, have been developed, further efforts to explore mechanistically distinct and complementary strategies are still critical to better treatment regimens. We previously showed that lentiviral vector-driven expression of Δ133p53α, a natural inhibitory isoform of p53, rescued HGPS patients-derived fibroblasts from early entry into cellular senescence, which is a downstream event of progerin-induced DNA damage. We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate Δ133p53α protein levels.

Methods: To investigate whether celastrol and ADZ1981 upregulate endogenous Δ133p53α in HGPS-derived fibroblasts and reduce their senescence-associated phenotypes, we performed western blot assays (Δ133p53α, progerin, and p21^WAF1, which mediates p53-induced senescence and is inhibited by Δ133p53α), senescence-associated β-galactosidase (SA-β-gal) staining, enzyme-linked immunosorbent assay (IL-6, which is a proinflammatory cytokine secreted from senescent cells), and qRT-PCR assays (p21^WAF1 and IL-6).

Results: Treatment with celastrol (0.1 μM for 24 h) or AZD1981 (10 μM for 24 h) reproducibly increased Δ133p53α expression and decreased p21^WAF1 expression in two strains of fibroblasts derived from HGPS patients. These compounds reduced the percentage of SA-β-gal-positive senescent cells and the secretion of IL-6 into culture medium in both of these fibroblast strains, irrespective of their different basal levels of senescence and IL-6 secretion. These compounds had no effect on the level of progerin.

Conclusion: Celastrol and ADZ1981 upregulate endogenous Δ133p53α and, reproducing the effects of its vector-driven expression, inhibit cellular senescence and IL-6 secretion in HGPS-derived fibroblasts. Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which Δ133p53α-regulated senescence plays a role.

Fibrotic disorders, such as idiopathic pulmonary fibrosis, are characterized by the accumulation of myofibroblasts, cells responsible for excessive extracellular matrix deposition and tissue remodeling. The inability to terminate this reparative process leads to persistent fibrosis with increasing age. GHK (glycyl-L-histidyl-L-lysine], a naturally occurring peptide, has demonstrated the potential in modulating fibrotic pathways by reversing cellular senescence and inducing apoptosis in myofibroblasts. GHK promotes tissue regeneration and enhances wound healing by activating stemness markers like p63 and PCNA. In aging, GHK's effect on pulmonary fibroblasts may restore youthful phenotypes, improving fibroblast migration and collagen contraction. This commentary discusses the role of GHK in resolving persistent fibrosis and the molecular mechanisms underpinning these effects, including integrin-β1 signaling. The potential of GHK as a therapeutic agent for fibrosis, including combination strategies with antioxidants or anti-inflammatory agents, is also explored.

Efficient and reproducible preclinical models for testing drugs or drug combinations that target aging are vital to develop a pipeline that results in a predictable outcome for geroscience research and geriatric medicine. Lifespan as a readout test in laboratory mice has been successful in identifying several drugs that robustly enhance healthy aging, and has provided impactful information for moving to clinical studies. However, it is a costly and time consuming process (about three years), and poorly designed to test drug combinations. Therefore, a more efficient pipeline is needed that would provide an increased number of drugs or drug combinations with promising and predictable outcomes for first in human studies in a shorter time frame. This editorial discusses an alternate system involving prescreening in an invertebrate model (the domestic house cricket) followed by short term cross sectional testing in aging mice. The time frame is about six months, and the system is simple enough to allow testing of multiple drugs concurrently. The cricket to mouse pipeline provides a logical and preclinical translational approach to identify drugs that have the potential to enhance human health at later ages of life.

Chronic neurodegenerative diseases pose a significant public health challenge due to their profound impact on individual autonomy and identity. Adult neurogenesis (ANG), the ongoing generation of neurons in specific brain regions, offers promising therapeutic avenues for these diseases. Despite controversies surrounding the existence and functional relevance of ANG in humans, emerging evidence suggests individual variability in ANG induction may hold the key to understanding and addressing these conditions. We advocate for a shift in research focus towards unraveling the genetic mechanisms governing ANG and understanding its functional significance in cognition. Novel models are needed to move this concept forward. The heterogeneous domestic house cricket (Acheta domesticus) has practical advantages and potential for rapid insights into neurogenesis. This model, coupled with advanced methodologies such as immunohistochemistry and RNA sequencing, can provide a detailed understanding of ANG and its therapeutic potential. Ultimately, embracing innovative models and holistic approaches to ANG research will help unlock new strategies for treating and preventing chronic neurodegenerative diseases.

Alzheimer's disease (AD) is a complex neurodegenerative disease and a leading cause of morbidity and mortality. Efforts to find disease modifying treatments have met with limited success. The naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine), in its Cu-bound form, supports angiogenesis, remodeling, and tissue repair, has anti-inflammatory and antioxidant properties, and has been shown to improve cognitive performance in aging mice. These features raised the question of whether GHK-Cu could alleviate neurodegeneration observed in AD. Male and female 5xFAD transgenic mice on the C57BL/6J background at 4 months of age were given 15 mg/kg GHK-Cu intranasally 3 times per week for 3 months until 7 months of age. Results showed that intranasal GHK-Cu treatment delayed cognitive impairment, reduced amyloid plaques, and lowered MCP1-mediated inflammation levels in the frontal cortex and hippocampus. These observations provide the rationale for conducting additional studies to investigate the potential of GHK-Cu peptide as a promising treatment for AD.

To establish the optimal conditions for SA-β-galactosidase staining on frozen rat kidney tissue sections, we evaluated staining intensity, specificity, and consistency under several experimental conditions. We tested the effects of tissue freezing methods, fixative solutions and methods, section thickness, and duration of incubation time for SA-β-gal staining to obtain consistent results. This work was prompted by the emerging developments that strongly suggest the potential central roles of cellular senescence in aging and age-related diseases. To further examine the direct roles of senescent cell accumulation on age-related changes in various tissues and organs, it is essential to determine tissue localization and distribution, cell-type specificity, and direct correlations to histopathological changes. Furthermore, the recent advancements in molecular analyses, including spatial transcriptomics and MALDI-MSI spatial metabolomics, etc., on histology sections enable more in-depth and comprehensive analyses of underlying mechanisms to determine the roles that senescent cells play in age-related pathophysiology by integrating SA-β-gal stained tissue sections from the same samples. Based on our results, the following method showed the optimal SA-β-gal staining for frozen rat kidney sections: a) preparation of frozen blocks in OCT compound using a dry ice methanol bath; b) slides with both pre- and post-fixation method showed the most intense staining with clear tissue structural patterns; c) the staining areas and intensity were higher and specific with thicker (20 μm) tissue sections; and d) a 4-hour staining incubation period with both pre- and post-fixation method showed the optimal intensity and specificity. Although we established the optimal SA-β-galactosidase staining protocol with kidney, further evaluation is needed to determine the optimal staining conditions for other tissues. We believe that consistent and specific SA-β-galactosidase staining in frozen kidney sections will facilitate comparative analyses with new molecular imaging techniques to examine the exact roles of cellular senescence in aging and age-related pathology.

There has been little progress in reducing the incidence and mortality of Alzheimer's disease (AD). Prevention of onset, more accurate diagnostic tools, and prediction of health outcomes have all been identified as critical issues, but more and better basic research approaches are needed. The single greatest risk factor associated with AD is aging. It follows that if aging can be delayed, there should be an equivalent delay or even prevention of the onset of AD neuropathology. Therefore, targeting multiple pathways of aging would be a powerful way to enhance resilience to aging and slow or prevent the onset of AD neuropathology and dementia in a personalized manner. More effective and predictive animal models, such as the aging pet cat that spontaneously develops neuropathology similar to human AD patients, are necessary to help validate noninvasive and inexpensive biomarkers for identifying individuals at risk. Resilience to aging and its ability to delay or prevent the onset of age-related diseases should be the focus for preventing brain aging and enhancing resistance to AD.