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Unfortunately, any targeted therapy is, always, started with low levels of the drug in the organism, selecting for drug resistance. One should propose that initial drug levels must be maximized, and durations may be minimized, ideally, as portions of preemptive combination of targeted drugs.

Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces individual PFS in 15-20% of patients compared to first-generation TKIs. Since detecting a single resistant cell before treatment is usually impossible, osimertinib must be used in all patients as a first-line treatment, raising median PFS overall but harming some. The simplest remedy is a preemptive combination (PC) of osimertinib and gefitinib. A comprehensive PC (osimertinib, afatinib/gefitinib, and capmatinib) could dramatically increase PFS for 80% of patients compared to osimertinib alone, without harming anyone. This article also explores PCs for MET-driven lung cancer.

In January 2023, diagnosed with numerous metastases of lung cancer in my brain, I felt that I must accomplish a mission. If everything happens for a reason, my cancer, in particular, I must find out how metastatic cancer can be treated with curative intent. This is my mission now, and the reason I was ever born. In January 2023, I understood the meaning of life, of my life. I was born to write this article. In this article, I argue that monotherapy with targeted drugs, even when used in sequence, cannot cure metastatic cancer. However, preemptive combinations of targeted drugs may, in theory, cure incurable cancer. Also, I share insights on various topics, including rapamycin, an anti-aging drug that can delay but not prevent cancer, through my personal journey., Competing Interests: CONFLICTS OF INTEREST Author has no conflicts of interest to declare.

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., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Both individuals taking rapamycin, an anti-aging drug, and those not taking it will ultimately succumb to age-related diseases. However, the former, if administered disease-oriented dosages for a long time, may experience a delayed onset of such diseases and live longer. The goal is to delay a particular disease that is expected to be life-limiting in a particular person. Age-related diseases, quasi-programmed during development, progress at varying rates in different individuals. Rapamycin is a prophylactic anti-aging drug that decelerates early development of age-related diseases. I further discuss hyperfunction theory of quasi-programmed diseases, which challenges the need for the traditional concept of aging itself.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Rapamycin (sirolimus) and other rapalogs (everolimus) are anti-cancer and anti-aging drugs, which delay cancer by directly targeting pre-cancerous cells and, indirectly, by slowing down organism aging. Cancer is an age-related disease and, figuratively, by slowing down time (and aging), rapamycin may delay cancer. In several dozen murine models, rapamycin robustly and reproducibly prevents cancer. Rapamycin slows cell proliferation and tumor progression, thus delaying the onset of cancer in carcinogen-treated, genetically cancer-prone and normal mice. Data on the use of rapamycin and everolimus in organ-transplant patients are consistent with their cancer-preventive effects. Treatment with rapamycin was proposed to prevent lung cancer in smokers and former smokers. Clinical trials in high-risk populations are warranted.

Cancer therapy is limited by toxicity in normal cells and drug-resistance in cancer cells. Paradoxically, cancer resistance to certain therapies can be exploited for protection of normal cells, simultaneously enabling the selective killing of resistant cancer cells by using antagonistic drug combinations, which include cytotoxic and protective drugs. Depending on the mechanisms of drug-resistance in cancer cells, the protection of normal cells can be achieved with inhibitors of CDK4/6, caspases, Mdm2, mTOR, and mitogenic kinases. When normal cells are protected, the selectivity and potency of multi-drug combinations can be further enhanced by adding synergistic drugs, in theory, eliminating the deadliest cancer clones with minimal side effects. I also discuss how the recent success of Trilaciclib may foster similar approaches into clinical practice, how to mitigate systemic side effects of chemotherapy in patients with brain tumors and how to ensure that protective drugs would only protect normal cells (not cancer cells) in a particular patient.

At the very moment of cell-cycle arrest, the cell is not senescent yet. For several days in cell culture, the arrested cell is acquiring a senescent phenotype. What is happening during this geroconversion? Cellular enlargement (hypertrophy) and hyperfunctions (lysosomal and hyper-secretory) are hallmarks of geroconversion.

There is no doubt that prostate cancer is a disease. Then, according to hyperfunction theory, menopause is also a disease. Like all age-related diseases, it is a natural process, but is also purely harmful, aimless and unintended by nature. But exactly because these diseases (menopause, prostate enlargement, obesity, atherosclerosis, hypertension, diabetes, presbyopia and thousands of others) are partially quasi-programmed, they can be delayed by slowing aging. Is aging a disease? Aging is a quasi-programmed disease that is partially treatable by rapamycin. On the other hand, aging is an abstraction, a sum of all quasi-programmed diseases and processes. In analogy, the zoo consists of animals and does not exist without animals, but the zoo is not an animal.

Making provocative headlines, three outstanding publications demonstrated that early-life treatment with rapamycin, including treatments during developmental growth, extends lifespan in animals, confirming predictions of hyperfunction theory, which views aging as a quasi-program (an unintended continuation of developmental growth) driven in part by mTOR. Despite their high theoretical importance, clinical applications of two of these studies in mice, Drosophila and Daphnia cannot be implemented in humans because that would require growth retardation started at birth. A third study demonstrated that a transient (around 20% of total lifespan in Drosophila ) treatment with rapamycin early in Drosophila adult life is as effective as lifelong treatment, whereas a late-life treatment is not effective. However, previous studies in mice demonstrated that a transient late-life treatment is highly effective. Based on hyperfunction theory, this article attempts to reconcile conflicting results and suggests the optimal treatment strategy to extend human lifespan.

Competing Interests: CONFLICTS OF INTEREST Author has no conflicts of interest to declare.

A hallmark of cellular senescence is proliferation-like activity of growth-promoting pathways (such as mTOR and MAPK) in non-proliferating cells. When the cell cycle is arrested, these pathways convert arrest to senescence (geroconversion), rendering cells hypertrophic, beta-Gal-positive and hyperfunctional. The senescence-associated secretory phenotype (SASP) is one of the numerous hyperfunctions. Figuratively, geroconversion is a continuation of growth in non-proliferating cells. Rapamycin, a reversible inhibitor of growth, slows down mTOR-driven geroconversion. Developed two decades ago, this model had accurately predicted that rapamycin must extend life span of animals. However, the notion that senescent cells directly cause organismal aging is oversimplified. Senescent cells contribute to organismal aging but are not strictly required. Cell senescence and organismal aging can be linked indirectly via the same underlying cause, namely hyperfunctional signaling pathways such as mTOR.

A thought-provoking article by Gems and de Magalhães suggests that canonic hallmarks of aging are superficial imitations of hallmarks of cancer. I took their work a step further and proposed hallmarks of aging based on a hierarchical principle and the hyperfunction theory.To do this, I first reexamine the hallmarks of cancer proposed by Hanahan and Weinberg in 2000. Although six hallmarks of cancer are genuine, they are not hierarchically arranged, i.e., molecular, intra-cellular, cellular, tissue, organismal and extra-organismal. (For example, invasion and angiogenesis are manifestations of molecular alterations on the tissue level; metastasis on the organismal level, whereas cell immortality is observed outside the host).The same hierarchical approach is applicable to aging. Unlike cancer, however, aging is not a molecular disease. The lowest level of its origin is normal intracellular signaling pathways such as mTOR that drive developmental growth and, later in life, become hyperfunctional, causing age-related diseases, whose sum is aging. The key hallmark of organismal aging, from worms to humans, are age-related diseases. In addition, hallmarks of aging can be arranged as a timeline, wherein initial hyperfunction is followed by dysfunction, organ damage and functional decline.

Some visionaries prefer to dream of immortality rather than to actually live longer. Here I discuss how combining rapamycin with other modalities may let us live long enough to benefit from future discoveries in cellular reprogramming and what needs to be done at Atlos Labs to make this happen., Competing Interests: CONFLICTS OF INTEREST The author has no conflicts of interest to declare.

Although average human life expectancy is rising, the maximum lifespan is not increasing. Leading demographers claim that human lifespan is fixed at a natural limit around 122 years. However, there is no fixed limit in animals. In animals, anti-aging interventions (dietary restrictions, rapamycin, genetic manipulations) postpone age-related diseases and thus automatically extend maximum lifespan. In humans, anti-aging interventions have not been yet implemented. Instead, by treating individual diseases, medical interventions allow a patient to live longer (despite morbidity), expanding morbidity span. In contrast, slowly aging individuals (centenarians) enter very old age in good health, but, when diseases finally develop, they do not receive thorough medical care and die fast. Although the oldest old die from age-related diseases, death certificates often list "old age", meaning that diseases were not even diagnosed and even less treated. The concept of absolute compression of morbidity is misleading in humans (in truth, there is no other way to compress morbidity as by denying thorough medical care) and false in animals (in truth, anti-aging interventions do not condense morbidity, they postpone it). Anti-aging interventions such as rapamycin may potentially extend both healthspan and maximal lifespan in humans. Combining anti-aging medicine with cutting-edge medical care, regardless of chronological age, will extend maximal lifespan further., Competing Interests: CONFLICTS OF INTEREST The author has no conflicts of interest to declare.

Senolytics are basically anti-cancer drugs, repurposed to kill senescent cells selectively. It is even more difficult to selectively kill senescent cells than to kill cancer cells. Based on lessons of cancer therapy, here I suggest how to exploit oncogene-addiction and to combine drugs to achieve selectivity. However, even if selective senolytic combinations will be developed, there is little evidence that a few senescent cells are responsible for organismal aging. I also discuss gerostatics, such as rapamycin and other rapalogs, pan-mTOR inhibitors, dual PI3K/mTOR inhibitors, which inhibit growth- and aging-promoting pathways. Unlike senolytics, gerostatics do not kill cells but slow down cellular geroconversion to senescence. Numerous studies demonstrated that inhibition of the mTOR pathways by any means (genetic, pharmacological and dietary) extends lifespan. Currently, only two studies demonstrated that senolytics (fisetin and a combination Dasatinib plus Quercetin) extend lifespan in mice. These senolytics slightly inhibit the mTOR pathway. Thus, life extension by these senolytics can be explained by their slight rapamycin-like (gerostatic) effects., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2021 Blagosklonny.)

Failure of rapamycin to extend lifespan in DNA repair mutant and telomerase-knockout mice, while extending lifespan in normal mice, indicates that neither DNA damage nor telomere shortening limits normal lifespan or causes normal aging.

Although numerous drugs seemingly extend healthspan in mice, only a few extend lifespan in mice and only one does it consistently. Some of them, alone or in combination, can be used in humans, without further clinical trials., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2021 Blagosklonny.)

COVID-19 is not deadly early in life, but mortality increases exponentially with age, which is the strongest predictor of mortality. Mortality is higher in men than in women, because men age faster, and it is especially high in patients with age-related diseases, such as diabetes and hypertension, because these diseases are manifestations of aging and a measure of biological age. At its deepest level, aging (a program-like continuation of developmental growth) is driven by inappropriately high cellular functioning. The hyperfunction theory of quasi-programmed aging explains why COVID-19 vulnerability (lethality) is an age-dependent syndrome, linking it to other age-related diseases. It also explains inflammaging and immunosenescence, hyperinflammation, hyperthrombosis, and cytokine storms, all of which are associated with COVID-19 vulnerability. Anti-aging interventions, such as rapamycin, may slow aging and age-related diseases, potentially decreasing COVID-19 vulnerability.

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.

Designed a century ago to treat epilepsy, the ketogenic diet (KD) is also effective against obesity and diabetes. Paradoxically, some studies in rodents have found that the KD seemingly causes diabetes, contradicting solid clinical data in humans. This paradox can be resolved by applying the concept of starvation pseudo-diabetes, which was discovered in starved animals almost two centuries ago, and has also been observed in some rapamycin-treated rodents. Intriguingly, use of the KD and rapamycin is indicated for a similar spectrum of diseases, including Alzheimer's disease and cancer. Even more intriguingly, benevolent (starvation) pseudo-diabetes may counteract type 2 diabetes or its complications.

Rapamycin (Sirolimus) slows aging, extends life span, and prevents age-related diseases, including diabetic complications such as retinopathy. Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. This mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes. There is no indication that starvation (benevolent) pseudo-diabetes is detrimental. By contrast, it is associated with better health and life extension. In transplant patients, a weak association between rapamycin/everolimus use and hyperglycemia is mostly due to a drug interaction with calcineurin inhibitors. When it occurs in cancer patients, the hyperglycemia is mild and reversible. No hyperglycemic effects of rapamycin/everolimus have been detected in healthy people. For antiaging purposes, rapamycin/everolimus can be administrated intermittently (e.g., once a week) in combination with intermittent carbohydrate restriction, physical exercise, and metformin.

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.

This article has an addendum: The below information has been added to this article. https://crln.acrl.org/index.php/crlnews/article/view/16837/18434