Methuselah's Pathfinding Strategies
NEW PARTS FOR PEOPLE
Technologies that will create new organs, bones, vasculature (with the probable near-term exception of the brain).
New Parts For People
As we age, the wear and tear we put on our bodies begins to take a toll. As one body component begins to weaken, this leads to an exponential strain on the body that stresses remaining parts, leading to failure and eventual death. This strategy focuses on technologies that create replacement parts of our bodies, such as organs, cartilage, bones, and vasculature.
GET THE CRUD OUT
Safely remove senescent and other destructive biological structures, intercellular damage or waste (i.e. amyloid), etc.
Get The Crud Out
Cellular processes of life result in by-products that are harmful if not cleared by the cell. Lifestyle and environmental factors add to the gradual accumulation of toxic substances in the body. As we age, there is an increasing amount of DNA damage, which leads to ineffective cellular processes, intracellular damage, and senescent cells. Outside of the cell, wastes such as amyloids can accumulate, negatively affecting organ function. This strategy focuses on technologies that clear harmful substances from the body at both the microscopic (cellular), and macroscopic (organ) level. Destruction of ineffective or harmful cells, as well as removal of toxic proteins and metabolites is essential to the restoration of youthful health.
RESTORE THE RIVERS
Restore the circulatory system
to full competence.
Restore The Rivers
As an individual ages, the circulatory system becomes less effective due, in part, to vessel stiffening, less effective pumping, insufficient waste clearance, poor oxygen exchange, and inadequate angiogenesis. This strategy addresses the need to improve these factors in the aged, including accelerated angiogenesis, more effective carriage and transfer of vital particles, and restored function of the circulatory system to youthful competence.
DEBUG THE CODE
Restore the body's informational integrity and its accurate replication.
Debug the Code
Fundamentally, we are built from codes. As we go through life, insults and damage happen to this code. The code includes DNA, and also the "action code", RNA, and proteins that actually do the work of the cells. This strategy deals with the informational life of the cell and its expression. Over time these activities degrade with age. Our first goal is to create actionable metrics that can illuminate just what is happening in your cells due to changes in your habits, food intake, age, supplements you take, stresses from work and family life and etc. If you can't measure it you can't fix it. Once measured, we will need to return the code to a youthful state.
RESTOCK THE SHELVES
Replenish building blocks such as stem cells and immune system antibodies.
Restock The Shelves
Each person is constantly being dismantled, destroyed, and rebuilt at the cellular level. As we age, our ability to successfully "retire" harmful cells weakens, as does our ability to rebuild. Stem cells continue to be active and present in adult tissue but become fewer and less effective as we age. Senescent cells become more prolific, sapping and straining the body systems. Additionally, with advanced age comes a weakened immune system, due to a combination of more onslaughts to the body and less effective defenses. This strategy addresses the need to provide the aged body with the tools required to rebuild and protect.
LUST FOR LIFE
Restore the capacity for joy. For instance, rejuvenated senses and athletic competence.
Lust For Life
Among the aged, depression, loss of purpose, and social isolation are serious problems. Losing athletic competence often results in fear of injury, limited independence, and loneliness. Social isolation and physical disability lead to feelings of uselessness and hopelessness. Loss of acuity of the senses endangers the elderly and limits their ability to savor the little things in life that add up to happiness. This strategy addresses the need to help older ones to want to increase their longevity, and to empower them to make the most of longer life. By restoring the senses, cognition, and physical ability, older ones will be capable of independence and productivity. They will be free to explore the world and themselves through new experiences, friends, and skills.
REBUILD THE WALLS
Fortify and rebuild our walls. From the fascia that surround every nerve fiber to the skin that hold us all together.
Rebuild The Walls
The Largest Organ We Have is Under Attack. Our skin, cell walls, and every other barrier in our body is succumbing to decades of wear and tear. As we age, we experience decreased sensation, increased response time, chronic inflammation, and frailty. This strategy focuses on developing technologies that restore integrity and rebuild our walls, from the fascia that surround every nerve fiber to the skin that hold us all together.
Why These Strategies?
Aging, the progressive loss of physiological function, is the main risk for leading diseases and ultimately leads to death. The process of aging is complex, and when considering the vision of improving health and preventing and reversing the aging process, it is helpful to organize the strategies to address the 9 Hallmarks of Aging.
The seven strategies employed by the Methuselah Foundation and Everest Health address these 9 Hallmarks of aging so that we can make meaningful and measurable change to positively impact the decline associated with age.
12 Hallmarks of Aging
1
Genomic InstabilityAs we age, we accumulate damage to our genes. If our DNA is damaged, both basic and complex body functions break down.
Example: Cancers.
2
Telomere AttritionTelomeres are the portion of the DNA which allow replication. As we age, these telomeres shorten and eventually are unable to produce further copies.
Example: Senescent cell accumulation.
3
EPIGENETIC ALTERATIONSThroughout our lives, our environment and behaviors alter our DNA which deleteriously changes our ability to thrive.
Example: Lung disease.
4
Loss of proteostasisProteostasis is the process that maintains function of proteins within and outside the cell. Proteins are the building blocks of life at every level. When any one of these functions fails, we deteriorate in innumerous ways.
Example: Neurodegenerative disease.
5
Deregulated Nutrient SensingThese 4 pathways of nutrient sensing are essential to allow the cell to recognize and use nutrients for energy and function. When our cells cannot sense and use nutrients, the whole organism suffers.
Example: Metabolic syndrome.
6
Mitochondrial DysfunctionMitochondria are the powerhouse of the cell, ensuring energy is available to the whole body. When the cell lacks energy, basic functions become deranged, leading to failure of the whole body.
Example: Chronic fatigue.
7
Cellular SenescenceIt is a normal part of each cell's life cycle to turn itself off and die when it is no longer effective. As we age, many factors lead senescence accumulation, a state in which there are too many ineffective cells which do not turn themselves off, but remain in the body and cause damage.
Example: Muscle wasting and weakness.
8
Stem Cell ExhaustionStem cells are important for tissues to repair and regenerate. As stem cells replicate throughout life, they lose the ability to produce functional cells at the necessary rate.
Example: Poor immune function.
9
Altered Intracellular CommunicationWithin the cell and between cells, there are a multitude of signals which produce the necessary actions to support life. When we can no longer communicate at the intracellular level, there is a cascade of properties which cease to work as needed.
Example: Cardiovascular disease.
10
DISABLED MACROAUTHOPHAGYMacroautophagy is a cellular process responsible for removing and recycling damaged cell components and reduced organelle turnover. This accumulation of waste in our cells contributes to disease and accelerated aging.
Example: Osteoarthritis
11
CHRONIC INFLAMMATIONAlso known as "inflammaging", this is triggered by epigenetic DNA changes which stimulate overexpression of inflammatory proteins such as cytokines, interleukins, and prostaglandins.
Example: Immune system decline.
12
MICROBIOME DYSBIOSISDisruption of the diverse bacteria-host bidirectional communication results in dysbiosis and contributes to a variety of pathological conditions.
Example: Obesity
Of course, these hallmarks work in concert with one another. When just one of these hallmarks begins to fail, it challenges the others and often leads to multi-faceted failure of the organism. We see this often, with a severe or chronic disease leading to multiple comorbid diseases, and in the sudden and profound decline that many people experience at around age 70. We know the underlying issues, and they are the keys to identifying interventions that will prevent and repair decline, keep us functioning optimally, and able to effectively handle stressors to our systems.
Seminal Scientific Papers
Targeting ageing with rapamycin and its derivatives in humans: a systematic review
2024 Feb
Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18 400 unique articles, resulting in 19 included studies. Rapamycin and its derivatives improved physiological parameters associated with ageing in the immune, cardiovascular, and integumentary systems of healthy individuals or individuals with ageing-related diseases. Overall, no significant effects on the endocrine, muscular, or neurological systems were found. The effects of rapamycin or its derivatives on the respiratory, digestive, renal, and reproductive systems were not assessed. No serious adverse events attributed to rapamycin and its derivatives were reported in healthy individuals; however, there were increased numbers of infections and increases in total cholesterol, LDL cholesterol, and triglycerides in individuals with ageing-related diseases. Future studies should assess the remaining unexamined systems and test the effects of long-term exposure to rapamycin and its derivatives.
Evaluation of off-label rapamycin use to promote healthspan in 333 adults
2023 May 16
Rapamycin (sirolimus) is an FDA-approved drug with immune-modulating and growth-inhibitory properties. Preclinical studies have shown that rapamycin extends lifespan and healthspan metrics in yeast, invertebrates, and rodents. Several physicians are now prescribing rapamycin off-label as a preventative therapy to maintain healthspan. Thus far, however, there is limited data available on side effects or efficacy associated with use of rapamycin in this context. To begin to address this gap in knowledge, we collected data from 333 adults with a history of off-label use of rapamycin by survey. Similar data were also collected from 172 adults who had never used rapamycin. Here, we describe the general characteristics of a patient cohort using off-label rapamycin and present initial evidence that rapamycin can be used safely in adults of normal health status.
Targeting the biology of aging with mTOR inhibitors
2023 May 04
Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging.
Rapamycin improves Graves’ orbitopathy by suppressing CD4+ cytotoxic T lymphocytes
2022 Dec 29
CD4+ cytotoxic T lymphocytes (CTLs) were recently implicated in immune-mediated inflammation and fibrosis progression of Graves’ orbitopathy (GO). However, little is known about therapeutic targeting of CD4+ CTLs. Herein, we studied the effect of rapamycin, an approved mTOR complex 1 (mTORC1) inhibitor, in a GO mouse model, in vitro, and in patients with refractory GO. In the adenovirus-induced model, rapamycin significantly decreased the incidence of GO. This was accompanied by the reduction of both CD4+ CTLs and the reduction of orbital inflammation, adipogenesis, and fibrosis. CD4+ CTLs from patients with active GO showed upregulation of the mTOR pathway, while rapamycin decreased their proportions and cytotoxic function. Low-dose rapamycin treatment substantially improved diplopia and the clinical activity score in steroid-refractory patients with GO. Single-cell RNA-Seq revealed that eye motility improvement was closely related to suppression of inflammation and chemotaxis in CD4+ CTLs. In conclusion, rapamycin is a promising treatment for CD4+ CTL-mediated inflammation and fibrosis in GO.
Sarcoidosis Incidence after mTOR Inhibitor Treatment
2022 Sep 25
Objective: Mechanistic target of rapamycin (mTOR) inhibitors are effective in animal models of granulomatous disease, but their benefit in sarcoidosis patients is unknown. We evaluated the incidence of sarcoidosis in patients treated with mTOR inhibitors versus calcineurin inhibitors. Methods: This was a cohort study using the Optum Clinformatics® Data Mart (CDM) Database (2003–2019), IBM®MarketScan® Research Database (2006–2016), and Danish health and administrative registries (1996–2018). Patients aged ≥18 years with ≥1 year continuous enrollment before and after kidney, liver, heart, or lung transplant treated with an mTOR inhibitor or calcineurin inhibitor were included. Patients diagnosed with sarcoidosis before, or up to 90 days after, transplant were excluded. The incidence of sarcoidosis by treatment group was calculated. Results: In the Optum CDM/IBM MarketScan cohort, 1,898 patients were treated with an mTOR inhibitor (mean age 49 years; 34% female) and 9,894 patients were treated with a calcineurin inhibitor (mean age 50 years; 37% female). The mean follow-up in the mTOR inhibitor group was 1.1 years, with no incident sarcoidosis diagnosed. In the calcineurin inhibitor group, the mean follow-up was 2.2 years, with 12 incident sarcoidosis cases diagnosed. In the Danish cohort, 230 patients were treated with an mTOR inhibitor (mean age 49; 45% female), with no incident sarcoidosis diagnosed. There were 3,411 patients treated with a calcineurin inhibitor (mean age 45; 40% female), with 10 incident cases of sarcoidosis diagnosed. Conclusions: This study indicates a potential protective effect of mTOR inhibitor treatment compared with calcineurin inhibitor treatment against the development of sarcoidosis.
Sirolimus as a second-line treatment for Graves’ orbitopathy
2022 Jul 13
Objectives: A beneficial effect of sirolimus in Graves’ orbitopathy (GO) was reported, suggesting a possible use in clinical practice. We conducted an observational, single-centre, no-profit, clinical study to investigate the efficacy of sirolimus as a second-line treatment for moderate-to-severe, active GO compared with methylprednisolone. Methods: Data from consecutive patients given sirolimus (2 mg orally on first day, followed by 0.5 mg/day for 12 weeks) or methylprednisolone [500 mg iv/weekly (6 weeks), 250 mg/weekly (6 weeks)] as a second-line treatment were collected and compared. Primary objective: overall GO outcome at 24 weeks, based on a composite evaluation. Secondary objectives at 24 weeks: (1) improvement in quality of life, evaluated using a specific uestionnaire (GO-QoL); (2) reduction in proptosis; (3) reduction in the clinical activity score (CAS); (4) improvement of eye ductions; and (5) reduction in eyelid aperture. Results: Data from 30 patients (15 per group) treated between January 15, 2020, and June 15, 2021, were analysed. Proportion of GO responders (primary outcome) at 24 weeks was significantly greater in sirolimus group compared with methylprednisolone group (86.6% vs 26.6%; OR: 17.8; 95% CI from 2.7 to 116.8; P = 0.0026). GO-quality of life (GO-QoL) score was greater in sirolimus group. Proportion of proptosis responders was greater in sirolimus group, as well as proportion of clinical activity score (CAS) responders. No serious adverse events were observed, with no differences between groups. Conclusions: Sirolimus seems to be an effective second-line treatment for GO. Further randomized clinical trials are needed to confirm our observations.
Cellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs
2022 Apr 10
Cellular senescence is defined as irreversible cell cycle arrest caused by various processes that render viable cells non-functional, hampering normal tissue homeostasis. It has many endogenous and exogenous inducers, and is closely connected with age, age-related pathologies, DNA damage, degenerative disorders, tumor suppression and activation, wound healing, and tissue repair. However, the literature is replete with contradictory findings concerning its triggering mechanisms, specific biomarkers, and detection protocols. This may be partly due to the wide range of cellular and in vivo animal or human models of accelerated aging that have been used to study senescence and test senolytic drugs. This review summarizes recent findings concerning senescence, presents some widely used cellular and animal senescence models, and briefly describes the best-known senolytic agents.
Flavonoids—Natural Gifts to Promote Health and Longevity
2022 Feb 16
The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids.
Sirolimus (rapamycin) for the targeted treatment of the fibrotic sequelae of Graves’ orbitopathy
2022 Feb 12
Background: Rapamycin (alternatively known as sirolimus) is a macrolide immunosuppressant commonly used for organ transplantation. It acts both on lymphocytes through the mechanistic target of rapamycin (mTOR) pathway to reduce their sensitivity to interleukin-2 (IL-2) and, importantly, also has anti-fibrotic properties by acting on myofibroblasts. The latter have been implicated in the pathogenesis of thyroid eye disease (TED). Aim: To describe successful treatment and reversal of extraocular muscle fibrosis in TED with sirolimus. Methods: Case report and literature review with clinic-pathological correlation. Results: A patient with Graves’ orbitopathy (GO) developed significant ocular motility restriction, which was unresponsive to steroids and conventional immunosuppression. Unlike these prior treatments, rapamycin therapy improved the diplopia and fields of binocular single vision over a period of months. There were no adverse effects directly attributable to the treatment. Conclusion: With its low renal toxicity and ability to specifically target the underlying fibrotic pathways in GO, rapamycin may prove a useful adjunct to standard immunosuppressive regimes. We encourage further reporting of case series or the instigation of controlled trial.
Microbiome and Human Aging: Probiotic and Prebiotic Potentials in Longevity, Skin Health and Cellular Senescence
2021 Dec 18
The role of the microbiome in human aging is important: the microbiome directly impacts aging through the gastrointestinal system. However, the microbial impact on skin has yet to be fully understood. For example, cellular senescence is an intrinsic aging process that has been recently associated with microbial imbalance. With age, cells become senescent in response to stress wherein they undergo irreversible growth arrest while maintaining high metabolic activity. An accumulation of senescent cells has been linked to various aging and chronic pathologies due to an overexpression of the senescence-associated secretory phenotype (SASP) comprised of proinflammatory cytokines, chemokines, growth factors, proteases, lipids and extracellular matrix components. In particular, dermatological disorders may be promoted by senescence as the skin is a common site of accumulation. The gut microbiota influences cellular senescence and skin disruption through the gut-skin axis and secretion of microbial metabolites. Metabolomics can be used to identify and quantify metabolites involved in senescence. Moreover, novel anti-senescent therapeutics are warranted given the poor safety profiles of current pharmaceutical drugs. Probiotics and prebiotics may be effective alternatives, considering the relationship between the microbiome and healthy aging. However, further research on gut composition under a senescent status is needed to develop immunomodulatory therapies.
Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials
2021 Sep 14
GLP-1 receptor agonists reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes. However, uncertainty regarding kidney outcomes persists and whether benefits extend to exendin-4-based GLP-1 receptor remains uncertain. We aimed to meta-analyse the most up-to-date evidence on the cardiovascular benefits and risks of GLP-1 receptor agonists from outcome trials in patients with type 2 diabetes.
Inhibition of Fibrotic Contraction by Sirolimus (Rapamycin) in an Ex Vivo Model of Thyroid Eye Disease
2021 Jul
Background: Thyroid eye disease (TED) is characterized by orbital inflammation and complicated by extraocular muscle fibrosis. Treatment with rapamycin/sirolimus has been reported to improve ocular motility and disease manifestations in TED. Whether this resulted from a primary antifibrotic effect on fibroblasts or was secondary to immune-suppression is unclear. Methods: In vitro contractility studies of primary orbital fibroblasts. Cells from patients with TED and controls were treated with rapamycin [mechanistic target of rapamycin an (mTOR) inhibitor] and MHY1485 (an mTOR stimulator) as well as inhibitors upstream in the same signaling cascade (saracatinib and befatinib). Results: At concentrations consistent with the therapeutic dosing range in humans, rapamycin/sirolimus significantly reduces fibrosis in orbital fibroblasts from TED patients and controls in vitro. This effect is separate from, and in addition to, its immune suppressive effect. mTOR-driven fibrotic activity is greater in TED-derived fibroblasts and can be blocked also upstream of mTOR by inhibition of src. There was no adverse effect on cell survival. Conclusion: The authors present evidence for a direct antifibrotic effect of rapamycin/sirolimus in primary orbital fibroblasts. Targeting mTOR signaling presents a further and adjunctive treatment of TED alongside other immune-suppressive agents. By acting downstream of IGF1-R, sirolimus may offer a cost-effective alternative to teprotumumab therapy. Clinical case reports, now supplemented by this in vitro evidence, support the initiation of a clinical trial to treat the fibrotic sequelae of TED with this already-approved agent. Such an “off-the-shelf” therapy is a welcome prospect for TED treatment, particularly one available at a low price.
Successful Response to Treatment with Sirolimus in Pulmonary Sarcoidosis
2020 Nov 01
A 61-year-old nonsmoking Caucasian man presented with chronic cough, which led him to retire from his career as a physician prematurely. His physical exam and spirometry were normal. Chest computed tomography scan revealed mediastinal and hilar lymphadenopathy associated with bilateral mid-upper lung zone–predominant perilymphatic nodularity. Bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration revealed cobblestoning of the airways and nonnecrotizing granulomatous inflammation, consistent with the diagnosis of sarcoidosis. Over the next 24 months, the patient underwent trials of high-dose inhaled corticosteroids, bronchodilators, systemic corticosteroids, mucolytics, and cough suppressants with little relief in his symptoms. The patient exhibited mild reduction in cough with systemic corticosteroids, but repeated attempts to taper below 15 mg/d of prednisone were associated with recurrence of symptoms. Based on the recent evidence suggesting a role for activated mTOR (mechanistic target of rapamycin) signaling in the pathogenesis of sarcoidosis (1), a shared decision was made to pursue an off-label trial of sirolimus. After 10 months on 2 mg sirolimus daily, his cough had largely resolved, and his computed tomography scan demonstrated improved perilymphatic nodularity.
Is Caloric Restriction Associated with Better Healthy Aging Outcomes? A Systematic Review and Meta-Analysis of Randomized Controlled Trials
2020 Jul 30
Global dietary patterns have gradually shifted toward a ‘western type’ with progressive increases in rates of metabolic imbalance. Recently, animal and human studies have revealed positive effects of caloric restriction (CR) on many health domains, giving new knowledge for prevention of ill and health promotion; Methods: We conducted a systematic review (SR) of randomized controlled trials (RCTs) investigating the role of CR on health status in adults. A meta-analysis was performed on anthropometric, cardiovascular and metabolic outcomes; Results: A total of 29 articles were retrieved including data from eight RCTs. All included RCTs were at low risk for performance bias related to objective outcomes. Collectively, articles included 704 subjects. Among the 334 subjects subjected to CR, the compliance with the intervention appeared generally high. Meta-analyses proved benefit of CR on reduction of body weight, BMI, fat mass, total cholesterol, while a minor impact was shown for LDL, fasting glucose and insulin levels. No effect emerged for HDL and blood pressure after CR. Data were insufficient for other hormone variables in relation to meta-analysis of CR effects; Conclusion: CR is a nutritional pattern linked to improved cardiometabolic status. However, evidence is limited on the multidimensional aspects of health and requires more studies of high quality to identify the precise impact of CR on health status and longevity.
Compounds that extend longevity are protective in neurodegenerative diseases and provide a novel treatment strategy for these devastating disorders
2020 Jun 28
While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. In the inherited forms of these diseases, the disease-causing mutation is present from birth but symptoms appear decades later. This indicates that these mutations are well tolerated in younger individuals but not in older adults. Based on this observation, we hypothesized that changes taking place during normal aging make the cells in the brain (and elsewhere) susceptible to the disease-causing mutations. If so, then delaying some of these age-related changes may be beneficial in the treatment of neurodegenerative disease. In this review, we examine the effects of five compounds that have been shown to extend longevity (metformin, rapamycin, resveratrol, N-acetyl-l-cysteine, curcumin) in four of the most common neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis). While not all investigations observe a beneficial effect of these compounds, there are multiple studies that show a protective effect of each of these lifespan-extending compounds in animal models of neurodegenerative disease. Combined with genetic studies, this suggests the possibility that targeting the aging process may be an effective strategy to treat neurodegenerative disease.
Rapamycin for longevity: opinion article
2019 Oct 4
From the dawn of civilization, humanity has dreamed of immortality. So why didn’t the discovery of the anti-aging properties of mTOR inhibitors change the world forever? I will discuss several reasons, including fear of the actual and fictional side effects of rapamycin, everolimus and other clinically-approved drugs, arguing that no real side effects preclude their use as anti-aging drugs today. Furthermore, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging: cancer, stroke, infarction, blindness and premature death. I will also discuss why it is more dangerous not to use anti-aging drugs than to use them and how rapamycin-based drug combinations have already been implemented for potential life extension in humans. If you read this article from the very beginning to its end, you may realize that the time is now.
Metformin and Aging: A Review
2019 Sep 13
Metformin is sometimes proposed to be an “anti-aging” drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for type 2 diabetics. Large prospective, placebo-controlled trials are planned, in pilot stage or running, to find a new use (or indication) for an aging population. As one of the metformin trials has “frailty” as its endpoint, similar to a trial with a plant-derived senolytic, the latter class of novel anti-aging drugs is briefly discussed. Concerns exist not only for vitamin B12 and B6 deficiencies, but also about whether there are adverse effects of metformin on individuals who try to remain healthy by maintaining cardiovascular fitness via exercise.
Association between vitamin D supplementation and mortality: systematic review and meta-analysis
2019 Aug 12
Vitamin D supplementation alone was not associated with all cause mortality in adults compared with placebo or no treatment. Vitamin D supplementation reduced the risk of cancer death by 15%. Additional large clinical studies are needed to determine whether vitamin D3 supplementation is associated with lower all cause mortality.
Sirolimus (rapamycin) for the targeted treatment of the fibrotic sequelae of Graves’ orbitopathy
2019 Feb 12
Background: Rapamycin (alternatively known as sirolimus) is a macrolide immunosuppressant commonly used for organ transplantation. It acts both on lymphocytes through the mechanistic target of rapamycin (mTOR) pathway to reduce their sensitivity to interleukin-2 (IL-2) and, importantly, also has anti-fibrotic properties by acting on myofibroblasts. The latter have been implicated in the pathogenesis of thyroid eye disease (TED). Aim: To describe successful treatment and reversal of extraocular muscle fibrosis in TED with sirolimus. Methods: Case report and literature review with clinic-pathological correlation. Results: A patient with Graves’ orbitopathy (GO) developed significant ocular motility restriction, which was unresponsive to steroids and conventional immunosuppression. Unlike these prior treatments, rapamycin therapy improved the diplopia and fields of binocular single vision over a period of months. There were no adverse effects directly attributable to the treatment. Conclusion: With its low renal toxicity and ability to specifically target the underlying fibrotic pathways in GO, rapamycin may prove a useful adjunct to standard immunosuppressive regimes. We encourage further reporting of case series or the instigation of controlled trial.
Clinical Experience of Sirolimus Regarding Efficacy and Safety in Systemic Lupus Erythematosus
2019 Feb 06
New treatment options constitute unmet needs for patients diagnosed with systemic lupus erythematosus (SLE). Inhibition of the mammalian target of rapamycin (mTOR) pathway by sirolimus, a drug approved and in clinical use to prevent transplant rejection, has shown promising effects in lupus animal models as well as in patients with both antiphospholipid syndrome and SLE. Sirolimus inhibits antigen-induced T cell proliferation and increases the number of circulating regulatory T cells. Recently, sirolimus was tested in an open label phase 1/2 trial, including 43 patients with active SLE, resistant or intolerant to conventional medications. The results were encouraging showing a progressive improvement, including mucocutaneous and musculoskeletal manifestations. At our university unit, we have more than 16 years’ experience of sirolimus as treatment for non-renal manifestations of SLE. Herein, we retrospectively evaluated data on tolerance, dosage, affected organ systems, disease activity measures, corticosteroid reduction, concomitant immunosuppressive therapies, and patient-reported outcome measures (PROMs) such as pain intensity, fatigue, well-being and quality-of-life (QoL) in 27 Caucasian patients with mildly active SLE. Musculoskeletal manifestation was the main reason for sirolimus treatment followed by skin involvement and leukocytopenia. Mean time on sirolimus was 47.1 (range 2–140) months. Decreasing global disease activity was observed, as measured by the clinical SLE disease activity index-2000, with a mean reduction of 2.5 points (range -10 to 0) and a corresponding mean reduction of the physician’s global assessment (0–4) of 0.64 (range -2 to 0). The mean daily dose of corticosteroids (prednisolone) was reduced by 3.3 mg (-12.5 to 0). Non-significant trends toward improvements of QoL and pain intensity were found. Serious side-effects were not seen during sirolimus treatment, but early withdrawal due to nausea (n = 4) and non-serious infections (n = 2) appeared. This observational study, including longtime real-life use of sirolimus in SLE, is the largest to date and it essentially confirms the results of the recent phase 1/2 trial. Our data indicate that sirolimus is efficient in patients with musculoskeletal SLE manifestations, particularly arthritis and tendinitis. Further randomized controlled trials evaluating the potential benefits of sirolimus in SLE are warranted, but should aim to enroll patients with shorter disease duration, less accrued damage, and more diverse ethnicities.
Dietary intake and blood concentrations of antioxidants and the risk of cardiovascular disease, total cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of prospective studies
2018 Nov 23
Higher dietary intake and/or blood concentrations of vitamin C, carotenoids, and α-tocopherol (as markers of fruit and vegetable intake) were associated with reduced risk of cardiovascular disease, total cancer, and all-cause mortality. These results support recommendations to increase fruit and vegetable intake, but not antioxidant supplement use, for chronic disease prevention.
Disease or not, aging is easily treatable
2018 Nov 17
Is aging a disease? It does not matter because aging is already treated using a combination of several clinically-available drugs, including rapamycin. Whether aging is a disease depends on arbitrary definitions of both disease and aging. For treatment purposes, aging is a deadly disease (or more generally, pre-disease), despite being a normal continuation of normal organismal growth. It must and, importantly, can be successfully treated, thereby delaying classic age-related diseases such as cancer, cardiovascular and metabolic diseases, and neurodegeneration.
Prolonging healthy aging: Longevity vitamins and proteins
2018 Oct 15
It is proposed that proteins/enzymes be classified into two classes according to their essentiality for immediate survival/reproduction and their function in long-term health: that is, survival proteins versus longevity proteins. As proposed by the triage theory, a modest deficiency of one of the nutrients/cofactors triggers a built-in rationing mechanism that favors the proteins needed for immediate survival and reproduction (survival proteins) while sacrificing those needed to protect against future damage (longevity proteins). Impairment of the function of longevity proteins results in an insidious acceleration of the risk of diseases associated with aging. I also propose that nutrients required for the function of longevity proteins constitute a class of vitamins that are here named “longevity vitamins.” I suggest that many such nutrients play a dual role for both survival and longevity. The evidence for classifying taurine as a conditional vitamin, and the following 10 compounds as putative longevity vitamins, is reviewed: the fungal antioxidant ergothioneine; the bacterial metabolites pyrroloquinoline quinone (PQQ) and queuine; and the plant antioxidant carotenoids lutein, zeaxanthin, lycopene, α- and β-carotene, β-cryptoxanthin, and the marine carotenoid astaxanthin. Because nutrient deficiencies are highly prevalent in the United States (and elsewhere), appropriate supplementation and/or an improved diet could reduce much of the consequent risk of chronic disease and premature aging.
Fisetin is a senotherapeutic that extends health and lifespan
2018 Sep 29
Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity.
Dietary Antioxidants, Circulating Antioxidant Concentrations, Total Antioxidant Capacity, and Risk of All-Cause Mortality: A Systematic Review and Dose-Response Meta-Analysis of Prospective Observational Studies
2018 Sep 20
The associations of various dietary or circulating antioxidants with the risk of all-cause mortality in the general population have not been established yet. A systematic search was performed in PubMed and Scopus, from their inception up to October 2017. Prospective observational studies reporting risk estimates of all-cause mortality in relation to dietary intake and/or circulating concentrations of antioxidants were included. Random-effects meta-analyses were conducted. Forty-one prospective observational studies (total n = 507,251) involving 73,965 cases of all-cause mortality were included. The RRs of all-cause mortality for the highest compared with the lowest category of circulating antioxidant concentrations were as follows: total carotenes, 0.60 (95% CI: 0.46, 0.74); vitamin C, 0.61 (95% CI: 0.53, 0.69); selenium, 0.62 (95% CI: 0.45, 0.79); β-carotene, 0.63 (95% CI: 0.57, 0.70); α-carotene, 0.68 (95% CI: 0.58, 0.78); total carotenoids, 0.68 (95% CI: 0.56, 0.80); lycopene, 0.75 (95% CI: 0.54, 0.97); and α-tocopherol, 0.84 (95% CI: 0.77, 0.91). The RRs for dietary intakes were: total carotenoids, 0.76 (95% CI: 0.66, 0.85); total antioxidant capacity, 0.77 (95% CI: 0.73, 0.81); selenium, 0.79 (95% CI: 0.73, 0.85); α-carotene, 0.79 (95% CI: 0.63, 0.94); β-carotene, 0.82 (95% CI: 0.77, 0.86); vitamin C, 0.88 (95% CI: 0.83, 0.94); and total carotenes, 0.89 (95% CI: 0.81, 0.97). A nonsignificant inverse association was found for dietary zinc, zeaxanthin, lutein, and vitamin E. The nonlinear dose-response meta-analyses demonstrated a linear inverse association in the analyses of dietary β-carotene and total antioxidant capacity, as well as in the analyses of circulating α-carotene, β-carotene, selenium, vitamin C, and total carotenoids. The association appeared to be U-shaped in the analyses of serum lycopene and dietary vitamin C. The present study indicates that adherence to a diet with high antioxidant properties may reduce the risk of all-cause mortality. Our results confirm current recommendations that promote higher intake of antioxidant-rich foods such as fruit and vegetables.
Association of loneliness with all-cause mortality: A meta-analysis
2018 Sep 20
Loneliness shows a harmful effect for all-cause mortality and this effect is slightly stronger in men than in women. Moreover, the impact of loneliness was independent from the quality evaluation of each article and the effect of depression.
Measurement of sirolimus concentrations in human blood using an automated electrochemiluminescence immunoassay (ECLIA): a multicenter evaluation
2017 Dec 05
Background: Therapeutic drug monitoring (TDM) of sirolimus is essential in transplant recipients. We evaluated the performance of a new electrochemiluminescence immunoassay (ECLIA) for measuring sirolimus concentrations in whole blood at five European laboratories. Methods: Study assessments included repeatability, intermediate precision and functional sensitivity (concentration at coefficient of variation [CV] of 20%) experiments. Method comparisons with liquid chromatography-tandem mass spectrometry (LC-MS/MS; reference method) and two immunoassays (chemiluminescent microparticle immunoassay [CMIA] and antibody-conjugated magnetic immunoassay [ACMIA]) were performed using native samples from patients with kidney transplants. Results: Imprecision testing CVs were ≤6.4% and ≤10.7% across the sirolimus concentration range for both repeatability and intermediate precision, respectively. The ECLIA showed excellent functional sensitivity: the CV did not reach 20%; the CV at the assay’s limit of quantitation (1.5 μg/L) was 7.0%. Agreement between the ECLIA and LC-MS/MS using native kidney samples was close, with weighted Deming regression analysis yielding a slope of 1.05, an intercept of 0.154 μg/L and a Pearson’s correlation coefficient (r) of 0.94, while Bland-Altman analysis showed a combined mean bias of 0.41 μg/L (±2 standard deviation [SD], −1.96 to 2.68). The ECLIA also showed good correlation with the two other immunoassays: the CMIA (slope=0.91, intercept=0.112 μg/L and r=0.89) and the ACMIA (slope=0.99, intercept=0.319 μg/L and r=0.97). Conclusions: The ECLIA showed good precision, functional sensitivity and agreement with other methods of sirolimus measurement used in clinical practice, suggesting that the assay is suitable for TDM in transplant recipients and provides an alternative to LC-MS/MS.
Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis
2017 20 Apr
Biological aging measures have been proposed as proxies for extension of healthy life span in trials of geroprotective therapies that aim to slow aging. Several methods to measure biological aging show promise but it is not known if these methods are sensitive to changes caused by geroprotective therapy. We conducted analysis of two proposed methods to quantify biological aging using data from a recently concluded trial of an established geroprotector, caloric restriction. We obtained data from the National Institute on Aging CALERIE randomized trial through its public-access biobank (https://calerie.duke.edu/). The CALERIE trial randomized N = 220 nonobese adults to 25% caloric restriction (n = 145; 11.7% caloric restriction was achieved, on average) or to maintain current diet (n = 75) for 2 years. We analyzed biomarker data collected at baseline, 12-, and 24-month follow-up assessments. We applied published biomarker algorithms to these data to calculate two biological age measures, Klemera–Doubal Method Biological Age and homeostatic dysregulation. Intent-to-treat analysis using mixed-effects growth models of within-person change over time tested if caloric restriction slowed increase in measures of biological aging across follow-up. Analyses of both measures indicated caloric restriction slowed biological aging. Weight loss did not account for the observed effects. Results suggest future directions for testing of geroprotective therapies in humans.
Health effects of intermittent fasting: hormesis or harm? A systematic review
2015 Jul 01
Clinical research studies of fasting with robust designs and high levels of clinical evidence are sparse in the literature. Whereas the few randomized controlled trials and observational clinical outcomes studies support the existence of a health benefit from fasting, substantial further research in humans is needed before the use of fasting as a health intervention can be recommended.
Sirolimus: The Evidence for Clinical Pharmacokinetic Monitoring
2012 Sep 30
This review seeks to apply a decision-making algorithm to establish whether clinical pharmacokinetic monitoring (CPM) of sirolimus (rapamycin) in solid organ transplantation is indicated in specific patient populations. The need for CPM of sirolimus, although a regulatory requirement in Europe, has not yet been firmly established in North America and other parts of the world. Sirolimus has demonstrated immunosuppressive efficacy in renal, pancreatic islet cell, liver and heart transplant recipients. The pharmacological response of immunosuppressive therapy with sirolimus cannot be readily evaluated; however, a relationship between trough blood sirolimus concentrations, area under the plasma concentration-time curve (AUC) and the incidence of rejection has been proposed. Furthermore, sirolimus can be measured in whole blood by several assays — high-performance liquid chromatography with detection by tandem mass spectrometry, or with ultraviolet detection, radioreceptor assay or microparticle enzyme immunoassay. Both experimental animal and clinical data suggest that adverse events and their associated severity are correlated with blood concentrations. To prevent rejection and minimise toxicity, a therapeutic range of 4–12 μg/L (measured via Chromatographic assays) is recommended when sirolimus is used in conjunction with ciclosporin. If ciclosporin therapy is discontinued, a target trough range of 12–20 (μg/L is recommended. Sirolimus pharmacokinetics display large inter- and intrapatient variability, which may change in specific patient populations due to disease states or concurrent immunosuppressants or other interacting drugs. Due to the long half-life of sirolimus, dosage adjustments would ideally be based on trough levels obtained more than 5–7 days after initiation of therapy or dosage change. Once the initial dose titration is complete, monitoring sirolimus trough concentrations weekly for the first month and every 2 weeks for the second month appears to be appropriate. After the first 2 months of dose titration, routine CPM of sirolimus is not necessary in all patients, but may be warranted to achieve target concentrations in certain populations of patients, but the frequency of further monitoring remains to be determined and should be individualised.
Toxicity and efficacy of sirolimus: Relationship to whole-blood concentrations
2000 Mar 17
Background: Sirolimus is a novel macrolide immunosuppressive drug with a mechanism of action distinct from that of both cyclosporine and tacrolimus. Recent clinical studies have demonstrated a decrease in acute rejection episodes in renal transplant patients receiving sirolimus compared with controls. The major toxicities associated with sirolimus treatment are thrombocytopenia and hyperlipidemia. In addition, concern has been raised by the higher serum creatinine levels noted in patients receiving sirolimus and cyclosporine compared with controls receiving cyclosporine and azathioprine. Objective: The objective of the present review is to summarize the efficacy and toxicity data for sirolimus. Special consideration is given to evidence that links these effects to dose or whole-blood concentrations of sirolimus. Results: The literature indicates that trough concentrations of sirolimus >15 ng/mL appear to be associated with a greater risk of both thrombocytopenia and hyperlipidemia, whereas trough sirolimus concentrations <6 ng/mL have been associated with an increased incidence of acute rejection. Conclusion: The evidence to date supports target trough sirolimus concentrations of 6 to 15 ng/mL in most patients. In higher-risk groups and patients receiving cyclosporine-sparing regimens, higher concentrations may be necessary to achieve similar efficacy.
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