A Blueprint for Characterizing Senescence.

Given the heterogeneity of senescent cells, our knowledge of both the drivers and consequences of cellular senescence in tissues and organs remains limited, as is our understanding of how this process could be harnessed for human health. Here we identified five broad areas that would help propel the field forward.

Geroscience: linking aging to chronic disease.

Mammalian aging can be delayed with genetic, dietary, and pharmacologic approaches. Given that the elderly population is dramatically increasing and that aging is the greatest risk factor for a majority of chronic diseases driving both morbidity and mortality, it is critical to expand geroscience research directed at extending human healthspan.

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease.

HYPOTHESIS: 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. KEY PREDICTIONS: 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). STRATEGY AND KEY RESULTS: 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. INTERPRETATION: 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.

Navigating the Landscape of Translational Geroscience in Canada: A Comprehensive Evaluation of Current Progress and Future Directions.

The inaugural Canadian Conferences on Translational Geroscience were held as 2 complementary sessions in October and November 2023. The conferences explored the profound interplay between the biology of aging, social determinants of health, the potential societal impact of geroscience, and the maintenance of health in aging individuals. Although topics such as cellular senescence, molecular and genetic determinants of aging, and prevention of chronic disease were addressed, the conferences went on to emphasize practical applications for enhancing older people's quality of life. This article summarizes the proceeding and underscores the synergy between clinical and fundamental studies. Future directions highlight national and global collaborations and the crucial integration of early-career investigators. This work charts a course for a national framework for continued innovation and advancement in translational geroscience in Canada.

The Role of the National Institute on Aging in the Development of the Field of Geroscience.

The conceptualization of the field of geroscience, which began about 10 years ago, marks, together with the publication of "The hallmarks of aging" (see López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Cell 153: 1194-1217, 2013), a significant watershed in the development of aging research. Based on a very simple and commonly accepted premise, namely, that aging biology is at the core the most significant risk factor for all chronic diseases affecting the elderly, geroscience became possible because of earlier significant developments in the field of aging biology. Here we describe the origins of the concept, as well as its current status in the field. The principles of geroscience provide an important new biomedical perspective and have spawned a significantly increased interest in aging biology within the larger biomedical scientific community.

Challenges in developing Geroscience trials.

Geroscience is becoming a major hope for preventing age-related diseases and loss of function by targeting biological mechanisms of aging. This unprecedented paradigm shift requires optimizing the design of future clinical studies related to aging in humans. Researchers will face a number of challenges, including ideal populations to study, which lifestyle and Gerotherapeutic interventions to test initially, selecting key primary and secondary outcomes of such clinical trials, and which age-related biomarkers are most valuable for both selecting interventions and predicting or monitoring clinical responses ("Gerodiagnostics"). This article reports the main results of a Task Force of experts in Geroscience.

Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization.

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.

Prospects for life span extension.

Life expectancy has increased dramatically in the United States and in much of the world in recent years and decades. The factors underlying this increase are incompletely understood and are undoubtedly complex. A question that drives current research is whether life expectancy can be further extended using current knowledge of modifiable risk factors. A still more challenging research focus is on the possibility that life expectancy might be further increased through knowledge gained from studies of the basic biology of aging and its genetic and environmental modifiers.

A central pacemaker that underlies the production of seasonal and sexually dimorphic social signals: functional aspects revealed by glutamate stimulation.

The cyclic enrichment of behavioral repertoires is a common event in seasonal breeders. Breeding males Brachyhypopomus gauderio produce electric organ discharge (EOD) rate modulations called chirps while females respond with interruptions. The electromotor system is commanded by a pacemaker nucleus (PN) which sets the basal rate and produces the rate modulations. We focused on identifying functional, seasonal and sexual differences in this nucleus in correlation to these differences in behavior. The in vivo response to glutamate injection in the PN was seasonal, sexually dimorphic and site specific. Non-breeding adults and breeding females injected in dorsal and ventral sites generated EOD rate increases and interruptions, respectively. Reproductive males added a conspicuous communication signal to this repertoire. They chirped repetitively when we injected glutamate in a very restricted area of the ventral-rostral nucleus, surprisingly one with a low number of relay cell somata. This study shows that the PN is functionally organized in regions in a caudal-rostral axis, besides the previously documented dorsal-ventral division. Functional regions are revealed by seasonal changes that annually provide this nucleus with the cellular mechanisms that allow the bursting activity underlying chirp production, only in males.

Moving geroscience from the bench to clinical care and health policy.

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.

Measuring biological aging in humans: A quest.

The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well-established clinical guidelines. Physicians are often forced to engage in cycles of "trial and error" that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are "aging faster" to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.

Geroscience in the Age of COVID-19.

The data on COVID-19 is clear on at least one point: Older adults are most vulnerable to hospitalization, disability and death following infection with the novel coronavirus. Therefore, therapeutically addressing degenerative aging processes as the main risk factors appears promising for tackling the present crisis and is expected to be relevant when tackling future infections, epidemics and pandemics. Therefore, utilizing a geroscience approach, targeting aging processes to prevent multimorbidity, via initiating broad clinical trials of potential geroprotective therapies, is recommended.

The release of sympathetic neurotransmitters is impaired in aged rats after an inflammatory stimulus: a possible link between cytokine production and sympathetic transmission.

Aging results in a general decline in the response to external insults, including acute inflammatory challenges. In young animals, the inflammatory response requires activation of the sympathetic system, including neurotransmitters such as ATP, and catecholamines (epinephrine and norepinephrine). To test whether aging affects activation of this axis, and whether this in turn might affect cytokine release, we administered lipopolysaccharide (LPS) i.p. to adult, middle-aged and aged Fisher 344 rats (6-, 15- and 23-month old, respectively) and evaluated the early (0-12h) serum levels of Neuropeptide-Y (NP-Y), ATP and vanillyl mandelic acid (VMA, as an indirect measurement of catecholamine levels). In addition, we evaluated the association between these factors and serum levels of the cytokines tumor necrosis factor-alpha (TNFalpha) and interleukin-10 (IL-10). Induction of both ATP and NP-Y was markedly reduced in the serum of aged animals, when compared to their younger counterparts, while induction of VMA was not affected by age. In spite of these changes, serum levels of TNFalpha and IL-10 were strongly hyper induced and delayed in aged rats. The results suggest that during aging there is a dysregulation in sympathetic neurotransmitter regulatory mechanisms, and this might play a role in the impairment of the inflammatory response.

Diminished acute phase response and increased hepatic inflammation of aged rats in response to intraperitoneal injection of lipopolysaccharide.

Aging is associated with a deterioration of the acute phase response to inflammatory challenges. However, the nature of these defects remains poorly defined. We analyzed the hepatic inflammatory response after intraperitoneal administration of lipopolysaccharide (LPS) given to Fisher 344 rats aged 6, 15, and 22-23 months. Induction of the acute phase proteins (APPs), haptoglobin, alpha-1-acid glycoprotein, and T-kininogen was reduced and/or retarded with aging. Initial induction of interleukin-6 in aged rats was normal, but the later response was increased relative to younger counterparts. An exacerbated hepatic injury was observed in aged rats receiving LPS, as evidenced by the presence of multiple microabscesses in portal tracts, confluent necrosis, higher neutrophil accumulation, and elevated serum levels of alanine aminotransferase, relative to younger animals. Our results suggest that aged rats displayed a reduced expression of APPs and increased hepatic injury in response to the inflammatory insult.

Sexual and seasonal plasticity in the emission of social electric signals. Behavioral approach and neural bases.

Behavior in electric fish includes modulations of a stereotyped electric organ discharge (EOD) in addition to locomotor displays. Gymnotiformes can modulate the EOD rate to produce signals that participate in different behaviors. We studied the reproductive behavior of Brachyhypopomus pinnicaudatus both in the wild and laboratory settings. During the breeding season, fish produce sexually dimorphic social electric signals (SES): males emit three types of chirps (distinguished by their duration and internal structure), and accelerations, whereas females interrupt their EOD. Since these SES imply EOD frequency modulations, the pacemaker nucleus (PN) is involved in their generation and constitutes the main target organ to explore seasonal and sexual plasticity of the CNS. The PN has two types of neurons, pacemakers and relays, which receive modulatory inputs from pre-pacemaker structures. These neurons show an anisotropic rostro-caudal and dorso-ventral distribution that is paralleled by different field potential waveforms in distinct portions of the PN. In vivo glutamate injections in different areas of the PN provoke different kinds of EOD rate modulations. Ventral injections produce chirp-like responses in breeding males and EOD interruptions in breeding females, whereas dorsal injections provoke EOD frequency rises in both sexes. In the non-breeding season, males and females respond with interruptions when stimulated ventrally and frequency rises when injected dorsally. Our results show that changes of glutamate effects in the PN could explain the seasonal and sexual differences in the generation of SES. By means of behavioral recordings both in the wild and in laboratory settings, and by electrophysiological and pharmacological experiments, we have identified sexual and seasonal plasticity of the CNS and explored its underlying mechanisms.

Metabolic Aspects of Aging.

Metabolic interventions involving undernutrition but not malnutrition (e.g., caloric restriction, CR) are effective strategies for improving both health and longevity in species ranging from lower organisms to nonhuman primates. Initial human trials to test the effects of sustained, reduced energy intake have yielded promising health benefits. Through intense research efforts in understanding the molecular mechanisms of CR, three cellular pathways have now been identified although the precise details remain unknown. More recently, circadian regulation has been recognized as a novel mediator for CR effects in mice. Harnessing the molecular insights into CR, novel nutritional interventions and pharmacological application of CR mimetics have been tested showing great promise in simultaneously improving metabolic function and providing overall health benefits. Additional research is needed to identify efficacious therapeutics that can be safely and practically translated to human studies in promoting healthspan.

Geroscience and the trans-NIH Geroscience Interest Group, GSIG.

Age is by far the major risk factor for most chronic diseases. This has been common knowledge since time immemorial. Aging encompasses the biological changes most often seen as declines of function and increasing burden of disease. The close linkage of these two has led people to believe that aging, like age, is immutable. It is only recently that research into the basic molecular and cellular mechanisms of aging has led to potential interventions that increase lifespan and appear to increase healthspan, as well. Geroscience is an interdisciplinary field that aims to understand the relationship between the biology of aging and the biology of age-related diseases. The "geroscience hypothesis" posits that manipulation of aging will delay (in parallel) the appearance or severity of many chronic diseases because these diseases share the same underlying major risk factor (age). The hope is that this will lead to health improvements in the older population with perhaps greater efficiency than can be achieved through the successful cure and management of diseases of aging as they arise individually or as comorbidities.With those concepts in mind, the Geroscience Interest Group (GSIG) was launched as a trans-institute interest group within the NIH in November 2012. Here, we discuss the genesis of the trans-NIH group and the most salient activities that have occurred in the last 5 years.

Integrating Frailty Research into the Medical Specialties-Report from a U13 Conference.

Although the field of frailty research has expanded rapidly, it is still a nascent concept within the clinical specialties. Frailty, conceptualized as greater vulnerability to stressors because of significant depletion of physiological reserves, predicts poorer outcomes in several medical specialties, including cardiology, human immunodeficiency virus care, and nephrology, and in the behavioral and social sciences. Lack of a consensus definition, proliferation of measurement tools, inadequate understanding of the biology of frailty, and lack of validated clinical algorithms for frail individuals hinders incorporation of frailty assessment and frailty research into the specialties. 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 program to review the current state of knowledge regarding frailty in the subspecialties and to highlight examples of integrating frailty research into the medical specialties. Research questions to advance frailty research into specialty medicine are proposed.