Strategies for late phase preclinical and early clinical trials of senolytics.

Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention. Early preclinical data using senolytics, agents that target senescent cells, show promising results in several aging and disease models. The first in-human trials using the senolytic combination of Dasatinib and Quercetin indicated reduced senescent cell burden in adipose tissue of diabetic kidney disease patients and improved physical function in patients with idiopathic pulmonary fibrosis. Clinical trials with other senolytics, including the flavonoid Fisetin and BCL-xL inhibitors, are underway. These results from preclinical and early clinical trials illustrate the potential of senolytics to alleviate age-related dysfunction and diseases. However, multiple clinical trials across different aging and disease models are desperately needed. Parallel trials across institutions through the Translational Geroscience Network are facilitating testing to determine whether senolytics can be translated into clinical application.

New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms.

The elderly population is increasing faster than other segments of the population throughout the world. Age is the leading predictor for most chronic diseases and disorders, multimorbidity, geriatric syndromes, and impaired ability to recover from accidents or illnesses. Enhancing the duration of health and independence, termed healthspan, would be more desirable than extending lifespan merely by prolonging the period of morbidity toward the end of life. The geroscience hypothesis posits that healthspan can be extended by targeting fundamental aging mechanisms, rather than attempting to address each age-related disease one at a time, only so the afflicted individual survives disabled and dies shortly afterward of another age-related disease. These fundamental aging mechanisms include, among others, chronic inflammation, fibrosis, stem cell/ progenitor dysfunction, DNA damage, epigenetic changes, metabolic shifts, destructive metabolite generation, mitochondrial dysfunction, misfolded or aggregated protein accumulation, and cellular senescence. These processes appear to be tightly interlinked, as targeting any one appears to affect many of the rest, underlying our Unitary Theory of Fundamental Aging Mechanisms. Interventions targeting many fundamental aging processes are being developed, including dietary manipulations, metformin, mTOR (mechanistic target of rapamycin) inhibitors, and senolytics, which are in early human trials. These interventions could lead to greater healthspan benefits than treating age-related diseases one at a time. To illustrate these points, we focus on cellular senescence and therapies in development to target senescent cells. Combining interventions targeting aging mechanisms with disease-specific drugs could result in more than additive benefits for currently difficult-to-treat or intractable diseases. More research attention needs to be devoted to targeting fundamental aging processes.

Senolytic drugs: from discovery to translation.

Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using a hypothesis-driven approach. SC accumulate with ageing and at causal sites of multiple chronic disorders, including diseases accounting for the bulk of morbidity, mortality and health expenditures. The most deleterious SC are resistant to apoptosis and have up-regulation of anti-apoptotic pathways which defend SC against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them to survive, despite killing neighbouring cells. Senolytics transiently disable these SCAPs, causing apoptosis of those SC with a tissue-destructive SASP. Because SC take weeks to reaccumulate, senolytics can be administered intermittently - a 'hit-and-run' approach. In preclinical models, senolytics delay, prevent or alleviate frailty, cancers and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic and skin disorders as well as complications of organ transplantation, radiation and cancer treatment. As anticipated for agents targeting the fundamental ageing mechanisms that are 'root cause' contributors to multiple disorders, potential uses of senolytics are protean, potentially alleviating over 40 conditions in preclinical studies, opening a new route for treating age-related dysfunction and diseases. Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation and alleviate frailty in humans. Clinical trials for diabetes, idiopathic pulmonary fibrosis, Alzheimer's disease, COVID-19, osteoarthritis, osteoporosis, eye diseases and bone marrow transplant and childhood cancer survivors are underway or beginning. Until such studies are done, it is too early for senolytics to be used outside of clinical trials.

Jean Laplanche: o trabalho da obra / Jean Laplanche: el trabajo de la obra / Jean Laplanche: the work of the literary work

A obra de Jean Laplanche é mais um fazer trabalhar do que um simples retorno a Freud. Chegou a hora de fazer trabalhar a obra do próprio Jean Laplanche. Que status tópico é atribuído ao complexo de Édipo e à angústia de castração? Podemos, com Jean Laplanche, recusar-lhes a dignidade do inconsciente? Podemos pretender construir uma teoria psicanalítica unitária que abrace a totalidade da vida psíquica? Como prolongar a pista de uma homologia entre a situação antropológica fundamental e a situação analítica? Da discussão à exploração, passando pela divergência, este texto prolonga anos de conversas e debates com Jean Laplanche(AU)

Jean Laplanche’s work is rather a way of working than a simple return to Freud. It’s time to put on Jean Laplanche’s work to work by itself. What’s the topic status given to the Oedipus complex and to the castration anxiety? Can we, with Jean Laplanche, refuse the dignity of unconscious? Can we intend to build an unitary psychoanalytic theory that embraces the totality of the mental life? How to extend the path of a homology between the fundamental anthropological situation and the analytical situation? From discussion to exploration, going through divergence, this paper extends years of talks and debates with Jean Laplanche(AU)

La obra de Jean Laplanche es más un hacer trabajar que un simples volver a Freud. Llego el momento de hacer trabajar a la obra del propio Jean Laplanche. Que status tópico es atribuido al complejo de Edipo y hacía la angustia de castración? Podemos, con Jean Laplanche, recusarles a la dignidad del inconsciente? Podemos pretender construir una teoría psicoanalítica unitaria que abrace a la totalidad de la vida psíquica? Como prolongar la pista de una homología entre la situación antropológica fundamental y la situación analítica? De la discusión hacía la exploración, pasando por la divergencia, este texto prolonga años de conversaciones y debates con Jean Laplanche(AU)

Jean Laplanche: o trabalho da obra / Jean Laplanche: el trabajo de la obra / Jean Laplanche: the work of the literary work

A obra de Jean Laplanche é mais um fazer trabalhar do que um simples retorno a Freud. Chegou a hora de fazer trabalhar a obra do próprio Jean Laplanche. Que status tópico é atribuído ao complexo de Édipo e à angústia de castração? Podemos, com Jean Laplanche, recusar-lhes a dignidade do inconsciente? Podemos pretender construir uma teoria psicanalítica unitária que abrace a totalidade da vida psíquica? Como prolongar a pista de uma homologia entre a situação antropológica fundamental e a situação analítica? Da discussão à exploração, passando pela divergência, este texto prolonga anos de conversas e debates com Jean Laplanche

Jean Laplanche’s work is rather a way of working than a simple return to Freud. It’s time to put on Jean Laplanche’s work to work by itself. What’s the topic status given to the Oedipus complex and to the castration anxiety? Can we, with Jean Laplanche, refuse the dignity of unconscious? Can we intend to build an unitary psychoanalytic theory that embraces the totality of the mental life? How to extend the path of a homology between the fundamental anthropological situation and the analytical situation? From discussion to exploration, going through divergence, this paper extends years of talks and debates with Jean Laplanche

La obra de Jean Laplanche es más un hacer trabajar que un simples volver a Freud. Llego el momento de hacer trabajar a la obra del propio Jean Laplanche. Que status tópico es atribuido al complejo de Edipo y hacía la angustia de castración? Podemos, con Jean Laplanche, recusarles a la dignidad del inconsciente? Podemos pretender construir una teoría psicoanalítica unitaria que abrace a la totalidad de la vida psíquica? Como prolongar la pista de una homología entre la situación antropológica fundamental y la situación analítica? De la discusión hacía la exploración, pasando por la divergencia, este texto prolonga años de conversaciones y debates con Jean Laplanche