Human trials exploring anti-aging medicines

Guarente, Leonard; Sinclair, David A.; Kroemer, Guido

doi:10.1016/j.cmet.2023.12.007

Cited by 19 publications

(8 citation statements)

References 162 publications

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“…The upregulation of Bcl-2 by metformin was also observed on colon-infiltrating CCR6 + CD4 + T-cells in our pilot clinical trial performed on ART-treated PWH 46 . This is consistent with the knowledge that metformin is used as an anti-aging medicine 83 . Most recent studies demonstrated the clinical benefits of Bcl-2 inhibitors (i.e., Venetoclax) in promoting VR purging [84][85][86][87] .…”

Section: Discussionsupporting

confidence: 92%

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4+ T-Cells by Decreasing Viral Release

Fert,

Richard,

Raymond Marchand

et al. 2024

Preprint

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The mechanistic target of rapamycin (mTOR) positively regulates multiple steps of the HIV-1 replication cycle. We previously reported that a 12-weeks supplementation of antiretroviral therapy (ART) with metformin, an indirect mTOR inhibitor used in type-2 diabetes treatment, reduced mTOR activation and HIV transcription in colon-infiltrating CD4+ T-cells, together with systemic inflammation in nondiabetic people with HIV-1 (PWH). Herein, we investigated the antiviral mechanisms of metformin. In a viral outgrowth assay performed with CD4+ T-cells from ART-treated PWH, and upon infection in vitro with replication-competent and VSV-G-pseudotyped HIV-1, metformin decreased virion release, but increased the frequency of productively infected CD4lowHIV-p24+ T-cells. These observations coincided with increased BST2/Tetherin (HIV release inhibitor) and Bcl-2 (pro-survival factor) expression, and improved recognition of productively infected T-cells by HIV-1 Envelope antibodies. Thus, metformin exerts pleiotropic effects on post-transcription/translation steps of the HIV-1 replication cycle and may be used to accelerate viral reservoir decay in ART-treated PWH.

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Section: Discussionsupporting

confidence: 92%

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4+ T-Cells by Decreasing Viral Release

Fert,

Richard,

Raymond Marchand

et al. 2024

Preprint

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“…Currently, there is a debate if it will be possible to develop anti-aging therapies which might increase health span and even extend the lifespan of elderly humans. Recently, Guarente et al [ 166 ] summarized the present clinical knowledge and ongoing trials on the eight most promising drug candidates for anti-aging medicines. Two of these drugs, i.e., metformin and rapamycin, are clinically utilized drugs which have been able to extend the lifespan of rodents [ 167 , 168 ].…”

Section: The Anti-aging Signaling Suppresses the Expression Of The Pd...mentioning

confidence: 99%

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

Salminen

2024

J Mol Med

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The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8+ T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8+ T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy. Key messages Senescent cells accumulate within tissues during aging and age-related diseases. Senescent cells are able to escape immune surveillance by cytotoxic immune cells. Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells. Age-related signaling stimulates the expression of PD-L1 protein in senescent cells. Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.

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“…Beyond these risk reduction programs, efforts are ongoing to implement lifestyle interventions that reduce accelerated aging in cancer survivors. It will be interesting to learn whether drugs that are currently evaluated for their potential antiaging effects in clinical trials [ 4 ] can be advantageously used in cancer survivors as well.…”

Section: Aging As a Consequence Of Cancer And Its Treatmentmentioning

confidence: 99%

“…Aging is the most important risk factor of malignant disease, the prevalence of which dramatically increases as adults age, reaching a peak around 85 or 90 years, when the incidence of new cancer diagnoses starts to decline and that of cardiovascular and other diseases ramps up [ 1 , 2 ]. Aging is, to some degree, modulable, meaning that chronological age (measured in years) and biological age (measured by biological tests and clinical status) can be uncoupled from each other [ 3 , 4 ]. A young biological age is linked to a reduced risk of malignant disease [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Aging and cancer

Montégut,

López-Otín,

Kroemer

2024

Mol Cancer

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Aging and cancer exhibit apparent links that we will examine in this review. The null hypothesis that aging and cancer coincide because both are driven by time, irrespective of the precise causes, can be confronted with the idea that aging and cancer share common mechanistic grounds that are referred to as ‘hallmarks’. Indeed, several hallmarks of aging also contribute to carcinogenesis and tumor progression, but some of the molecular and cellular characteristics of aging may also reduce the probability of developing lethal cancer, perhaps explaining why very old age (> 90 years) is accompanied by a reduced incidence of neoplastic diseases. We will also discuss the possibility that the aging process itself causes cancer, meaning that the time-dependent degradation of cellular and supracellular functions that accompanies aging produces cancer as a byproduct or ‘age-associated disease’. Conversely, cancer and its treatment may erode health and drive the aging process, as this has dramatically been documented for cancer survivors diagnosed during childhood, adolescence, and young adulthood. We conclude that aging and cancer are connected by common superior causes including endogenous and lifestyle factors, as well as by a bidirectional crosstalk, that together render old age not only a risk factor of cancer but also an important parameter that must be considered for therapeutic decisions.

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Human trials exploring anti-aging medicines

Cited by 19 publications

References 162 publications

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4+ T-Cells by Decreasing Viral Release

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4+ T-Cells by Decreasing Viral Release

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

Aging and cancer

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