Search

We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action.We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints).Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments.Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.

Geriatricians and others must embrace the emerging field of geroscience. Until recently geroscience research was pursued in laboratory animals, but now this field requires specialized expertise in the care of vulnerable older patients with multiple chronic diseases and geriatric syndromes, the population likely to benefit the most from emerging therapies. While chronological aging measures the inevitable passage of clock time that occurs equally for everyone, biological aging varies among individuals, and importantly, it is modifiable. Advances in our understanding of biological aging, the discovery of strategies for modifying its rate, and an appreciation of aging as a shared risk factor for chronic diseases have jointly led to the Geroscience Hypothesis. This hypothesis states that interventions modifying aging biology can slow its progression-resulting in the delay or prevention of the onset of multiple diseases and disorders. Here we wish to report on the Third Geroscience Summit held at National Institutes of Health on November 4-5, 2019, which highlighted the importance of engaging other disciplines including clinicians. Involvement by scientists with expertise in clinical trials, health outcomes research, behavioral and social sciences, health policy, and economics is urgently needed to translate geroscience discoveries from the bench to clinical care and health policy. Adding to the urgency of broadening this geroscience coalition is the emergence of biological aging as one the most important modifiable factors of COVID-19, combined with the inability of our society to once again recognize and confront aging as a priority and opportunity when facing these types of public health emergencies.

Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience-guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA-approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)-like study involving such candidate gerotherapeutics.

Although the field of frailty research has expanded rapidly, it is still a nascent concept within the clinical specialties. Frailty, conceptualized as increased vulnerability to stressors because of significant depletion of physiological reserves, predicts poorer outcomes in several medical specialties, including cardiology, HIV care, nephrology, and in the behavioral and social sciences. Incorporation of frailty assessment and frailty research into the specialties is hindered by a lack of a consensus definition, by the proliferation of measurement tools, inadequate understanding of the biology of frailty, and lack of validated clinical algorithms for patients who have frailty. In 2015, the American Geriatrics Society, the National Institute on Aging (NIA) and the Alliance for Academic Internal Medicine held a conference for awardees of the NIA sponsored ‘Grants for Early Medical/Surgical Specialists Transition into Aging Research (GEMSSTAR)’1 program to review the current state of the knowledge regarding frailty in the sub-specialties, as well as to highlight key examples of integrating frailty research into the medical specialties. Key research questions to advance frailty research into specialty medicine are proposed.

Aging is the major risk factor for both the development of chronic diseases and loss of functional capacity. Geroscience provides links among the biology of aging, the biology of disease, and the physiology of frailty, three fields where enormous progress has been made in the last few decades. While, previously, the focus was on the role of aging in susceptibility to disease and disability, the other side of this relationship, which is the contribution of disease to aging, has been less explored at the molecular/cellular level. Indeed, the role of childhood or early adulthood exposure to chronic disease and/or treatment on accelerating aging phenotypes is well known in epidemiology, but the biological basis is poorly understood. A recent summit co-organized by the National Institutes of Health GeroScience Interest Group and the New York Academy of Sciences explored these relationships, using three chronic diseases as examples: cancer, HIV/AIDS, and diabetes. The epidemiological literature clearly indicates that early exposure to any of these diseases and/or their treatments results in an acceleration of the appearance of aging phenotypes, including loss of functional capacity and accelerated appearance of clinical symptoms of aging-related diseases not obviously related to the earlier event. The discussions at the summit focused on the molecular and cellular relationships between each of these diseases and the recently defined molecular and cellular pillars of aging. Two major conclusions from the meeting include the desire to refine an operational definition of aging and to concomitantly develop biomarkers of aging, in order to move from chronological to physiological age. The discussion also opened a dialogue on the possibility of improving late-life outcomes in patients affected by chronic disease by including age-delaying modalities along with the standard care for the disease in question.

Cell proliferation requires the coordinate synthesis and degradation of many proteins. In addition to the well-characterized involvement of the proteasome in the degradation of several cell cycle-regulated proteins, it has been established that cysteine proteinases are also involved in the control of cell proliferation, but their role is currently not understood. By using both synthetic cysteine proteinase inhibitors and overexpression of T-kininogen (T-KG), a physiologically relevant cysteine proteinase inhibitor, we show that inhibition of cysteine proteinases results in a severe inhibition of the ERK pathway of signal transduction. Mechanistically, this effect appears to be the result of stabilization of the ERK phosphatase MKP-1, which leads to an enhanced dephosphorylation (and hence inactivation) of ERK molecules. These results are specific to cysteine proteinase inhibitors and are not observed when either serine proteinases or the proteasome are inhibited. We hypothesize that inhibition of cysteine proteinases in vivo leads to a dysregulation of the ERK pathway, which results in an inability of the cell to transmit to the nucleus the signals generated by the presence of growth factors, thus resulting in loss of cell proliferation. J. Cell. Biochem. 80:11–23, 2000. © 2000 Wiley-Liss, Inc.