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Life-limiting aging. (A) Normal Aging. Hyperfunctional (mTOR-driven) aging is life-limiting. It reaches a deadly threshold earlier than accumulating molecular damage does. (B) Premature aging syndromes. When artificially accelerated by gene knockouts, accumulation of molecular damage may become life-limiting. Adopted from ref. [10]).
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... clarify, molecular damage does accumulate. Furthermore, molecular damage would eventually kill the organism, unless the organism dies from hyperfunctional aging or, even more specifically, from mTOR-driven aging ( Figure 3). Aging due to molecular damage and due to cellular hyperfunctions [10]). ...
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... [4][5][6] Major mechanistic theories of aging, including the molecular damage and mutation accumulation (MA) theory and the hyperfunction and antagonistic pleiotropy (AP) theory of aging, have stimulated many studies to test predictions from each. [7][8][9][10][11][12][13][14] While the MA theory highlights the critical roles of molecular damages incurred over time during aging, the AP and hyperfunction theory posits that key anabolic processes keep running post-reproduction and/or become abnormally hyperactivated and thereby cause aging and age-related pathologies. [7][8][9] Such AP effects are features of several cellular anabolic signaling proteins, including insulin and mTOR (mechanistic target of rapamycin). ...
... [7][8][9][10][11][12][13][14] While the MA theory highlights the critical roles of molecular damages incurred over time during aging, the AP and hyperfunction theory posits that key anabolic processes keep running post-reproduction and/or become abnormally hyperactivated and thereby cause aging and age-related pathologies. [7][8][9] Such AP effects are features of several cellular anabolic signaling proteins, including insulin and mTOR (mechanistic target of rapamycin). Late-life dysregulation or hyperfunction of insulin-mTOR signaling can indeed contribute to aging and age-associated pathologies, including type 2 diabetes, cardiovascular diseases, and cancer. ...
... Based on new insights from C. elegans models, this view may imply reconciling and unifying the two prevalent mechanistic theories of aging (molecular damage versus mTOR hyperfunction). [7][8][9][10][11][12][13][14] Various sphingolipids have been shown to contribute to organismal aging and ageassociated pathologies. [60][61][62] We identify LPD-3 as a critical megaprotein regulator of the phospholipid-sphingolipid balance or rheostat, dysfunction of which can impact aging via insulin-mTOR hyperfunction. ...
Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.
... I will mention selective protection of normal cells from chemotherapy [13] and explain why anti-cancer drugs are also tumor promoters, whether carcinogens can be anticancer drugs [14]. I also will discuss aging and age-related diseases that are a continuation of developmental growth [10,15,16]. ...
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.
... And this leads to natural compromises in the form of trade-offs. This idea of constraint differs from traditional programmatic theories, as the very concept of triggered quasi-programmes resulting from run on implies the absence of biological constraint (Blagosklonny, 2006;Blagosklonny, 2021;de Magalhães, 2005;Gems, 2022;Maklakov and Chapman, 2019). ...
The evolutionary theory of aging, particularly antagonistic pleiotropy (AP), provides an account of the ultimate origins of aging. What remains unclear is the nature of the proximate mechanisms by which AP gives rise to diseases of aging, like cardiovascular disease and Alzheimer’s disease. Damage-centric theories focusing on loss of genetic and cellular function have been proposed, as well as programmatic theories focusing on unwanted gene and cellular function. The latter include the hyperfunction and developmental theory that view aging as the futile continuation, or run-on, of growth and developmental programmes into later life. Yet neither type of theory has performed well in explaining late-life disease aetiology, particularly with respect to disease onset, presentation and progression. What is proposed here in this review is a new programmatic theory of aging. We argue that the emergence of many specific diseases may involve quasi-programmes that are not the result of run-on, but rather are triggered by other factors in late life. Such triggers may be non-programmatic (e.g. infection, mechanical injury) or programmatic. Moreover, the consequent pre-pathological and pathological changes may in some cases trigger further changes, leading to futile and destructive cascades of quasi-programmes and pathology. The origins of triggered quasi-programmes can be traced to biological constraint i.e. the inability of organisms to optimise all functions at once. And, to some extent, the new theory presented here revises the understanding of AP. That is, because any gene can be triggered in an erroneous manner, every gene is potentially an AP gene that risks pathology, though level of risk varies according to constraint. To help validate the theory, we test it against several complex diseases of aging. The new model in this review attempts to provide a blueprint understanding that, to a certain extent, closes the gap in the causal chain of events between evolutionary causes of aging and the aetiology of age-related diseases. It also helps to explain why certain disorders mimic accelerated aging and how interventions, such as the suppression of IIS and mTOR retard many aspects of aging; notably, though, unlike prior programmatic theories, the new theory is not mTOR-centric. Finally, it provides new perspectives on possible treatment of aging.
... This idea of constraint differs from traditional programmatic theories, as the very concept of triggered quasi-programmes resulting from run on implies the absence of biological constraint (Blagosklonny, 2006;Blagosklonny, 2021;de Magalhães, 2005;Gems, 2022;Maklakov and Chapman, 2019). ...
The evolutionary theory of aging, particularly antagonistic pleiotropy (AP), provides an account of the ultimate origins of aging. What remains unclear is the nature of the proximate mechanisms by which AP gives rise to diseases of aging, like cardiovascular disease and Alzheimer’s disease. Damage-centric theories focusing on loss of genetic and cellular function have been proposed, as well as programmatic theories focusing on unwanted gene and cellular function. The latter include the hyperfunction and developmental theory that view aging as the futile continuation, or run-on, of growth and developmental programmes into later life - controlled by nutrient-sensitive pathways like the mechanistic Target of Rapamycin (mTOR) and the linked insulin/IGF-1 signalling (IIS) pathway. Yet neither type of theory has performed well in explaining late-life disease aetiology, particularly with respect to disease onset, presentation and progression. What is proposed in this essay is a new programmatic theory of aging. This essay argues that the emergence of many specific diseases may involve quasi-programmes that are not the result of run-on, but rather are triggered by other factors in late life. Such triggers may be non-programmatic (e.g. infection, mechanical injury) or programmatic. Moreover, the consequent pre-pathological and pathological changes may in some cases trigger further changes, leading to futile and destructive cascades of quasi-programmes and pathology. The origins of triggered quasi-programmes can be traced to biological constraint i.e. the inability of organisms to optimise all functions at once. And, to some extent, the new theory presented here revises the understanding of AP. That is, because any gene can be triggered in an erroneous manner, every gene is potentially an AP gene that risks pathology, though level of risk varies according to constraint. To help validate the theory, we test it against several complex diseases of aging. The new model in this essay attempts to provide a blueprint understanding that, to a certain extent, closes the gap in the causal chain of events between evolutionary causes of aging and the aetiology of age-related diseases. It also helps to explain why certain disorders mimic accelerated aging and how interventions, such as the suppression of IIS and mTOR retard many aspects of aging; notably, though, unlike prior programmatic theories, the new theory is not mTOR-centric. Finally, it provides new perspectives on possible treatment of aging.
... Quasi-programs provide no benefit. As previously discussed, these quasi-programmed are driven by hyperfunctional cells, signaling pathways and systems (see for references [26][27][28]. Without discussing these topics here, it is noteworthy that SASP (hypersecretion) and pro-inflammation are typical hyperfunctions [29,30]. ...
... Age-related diseases (ARDs) in turn lead to secondary loss of functions and organ failure (late manifestations of aging) [23]. Hyperfunction theory explains why quasi-programmed aging is life-limiting, whereas accumulation of molecular damage is not life-limiting [23,26]. AGING According to hyperfunction theory, aging is a common driving cause of all ARDs, not just a risk factor ( Figure 1B). ...
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.
... Senolytic drug development is a common routine practice in the research area of oncology related sciences. Senolytics are approved as either chemotherapy agents (dasatinib, venetoclax) or cancerpreventing substances (Fisetin and Quercetin) (Blagosklonny 2021a). Killing of senescent cells and/ or ameliorating their detrimental SASP-related effects are currently considered to be effective gerotherapeutic approaches for fighting against age-related disorders. ...
... Killing of senescent cells and/ or ameliorating their detrimental SASP-related effects are currently considered to be effective gerotherapeutic approaches for fighting against age-related disorders. There are seven classes of senolytics: kinase inhibitors, a Bcl-2 family inhibitors, natural compounds, a p53 binding inhibitor, heat shock protein 90 inhibitors, UBX0101, and a histone deacetylase inhibitor (Niedernhofer and Robbins 2018;Yousefzadeh et al. 2018;Blagosklonny 2021a). ...
... Gerostatics also slow down cellular geroconversion to senescence but gerostatics do not necessarily target formation of SASP and they mostly act on non-senescent cells. (Walters et al. 2016;Blagosklonny 2021a). ...
Initially, endosymbiotic relation of mitochondria and other cellular compartments had been continued mutually. However, that evolutionary adaptation impaired because of the deterioration of endosymbiotic crosstalk due to aging and several pathological consequences in cellular redox status are seen, such as deterioration in redox integrity of mitochondria, interfered inter-organelle redox signaling and inefficient antioxidant response element mediated gene expression. Although the dysfunction of mitochondria is known to be a classical pattern of senescence, it is unresolved that why dysfunctional mitochondria is the core of senescence-associated secretory phenotype (SASP). Redox impairment and SASP-related disease development are generally together with weaken immunity. Impaired mitochondrial redox integrity and its ineffectiveness in immunity control render elders to be more prone to age-related diseases. As senotherapeutic agents, senolytics remove senescent cells whilst senomorphics/senostatics inhibits the secretion of SASP. Senotherapeutics and the novel approaches for ameliorating SASP-related unfavorable effects are recently thought to be promising ways as mitochondria-targeted gerotherapeutic options.
... In humans, the increase in prostate size is known as benign prostatic hyperplasia (Berges and Oelke, 2011;Zhang et al., 2013), however prostate size varies among ethnic groups and so does the rate of change with age (i.e., Bolivian Tsimane, Trumble et al., 2015) or the occurrence of enlarged prostates in older males (Mubenga et al., 2020). Some theory predicts that the enlargement of the prostate is a side-effect of cellular hyperfunction that causes ageing of this tissue (Blagosklonny, 2021). The hyperfunction theory of ageing proposes that suboptimal nutrientsensing molecular signaling in late-life causes ageing via excessive biosynthesis, as opposed to energy-tradeoffs (Lind et al., 2019). ...
Reproductive ageing can occur due to the deterioration of both the soma and germline. In males, it has mostly been studied with respect to age-related changes in sperm. However, the somatic component of the ejaculate, seminal fluid, is also essential for maintaining reproductive function. Whilst we know that seminal fluid proteins (SFPs) are required for male reproductive success across diverse taxa, age-related changes in SFP quantity and composition are little understood. Additionally, only few studies have explored the reproductive ageing of the tissues that produce SFPs, and the resulting reproductive outcomes. Here we provide a systematic review of studies addressing how advancing male age affects the production and properties of seminal fluid, in particular SFPs and oxidative stress, highlighting many open questions and generating new hypotheses for further research. We additionally discuss how declines in function of different components of seminal fluid, such as SFPs and antioxidants, could contribute to age-related loss of reproductive ability. Overall, we find evidence that ageing results in increased oxidative stress in seminal fluid and a decrease in the abundance of various SFPs. These results suggest that seminal fluid contributes towards important age-related changes influencing male reproduction. Thus, it is essential to study this mostly ignored component of the ejaculate to understand male reproductive ageing, and its consequences for sexual selection and paternal age effects on offspring.
... A quasi-program is a purposeless continuation of programs that were not turned off upon their completion. This has been discussed in detail [9,50,[71][72][73][74][75]. ...
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.
... Hyperfunction is a function that was not turned off upon its completion [58]. (Note: Hyperfunction is not necessarily an absolute increase in function but may even be a decrease if it is still higher than optimal for longevity [59]). For example, mTOR drives cellular growth, but when the cell cycle is blocked, and mTOR is not turned down, then it drives the senescence phenotype associated with hyperfunctions such as SASP and proinflammation [60]. ...
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.
... Detailed mechanisms of how phenoptosis is executed remain to be further elucidated, and may involve actions of proteases, lipid metabolic enzymes and the insulin pathway. In addition, while it is still debated whether natural aging may be driven primarily by biological damage accumulation, decline of cellular maintenance programs or hyperfunction of antagonistic pleiotropy genes [62][63][64][65][66], these seemingly divergent causes can be considered as chronic stresses that may contribute to natural aging and organismic death via chronic stress-induced phenoptosis (figure). It is conceivable that the paradigm of cold-thermal stress-induced phenoptosis in C. elegans may be an acute manifestation of such chronic stress-induced phenoptosis during aging. ...
... Further, as aging is considered as a progressive pathologic process, aspects of which can be driven by various types of chronic stress including bio-molecular cellular damages and inf lammatory stresses, important questions arise as how and to what degrees aging pathologies are determined by stochastic accumulation of molecular damages versus hyperfunction of genes and pathways with antagonistic pleiotropy effects [62][63][64][65][66]. While answers to these questions may well be species-specific, exploration of these issues should help revise or refine current models and guide future studies to understand both the mechanistic basis and evolutionary implications of stress-induced phenoptosis as well as natural aging. ...
Evolution by natural selection results in biological traits that enable organismic adaptation and survival under various stressful environments. External stresses can be sometimes too severe to overcome, leading to organismic death either because of failure in adapting to such stress, or alternatively, through a regulated form of organismic death (phenoptosis). While regulated cell deaths, including apoptosis, have been extensively studied, little is known about the molecular and cellular mechanisms underlying phenoptosis and its evolutionary significance for multicellular organisms. In this article, we review documented phenomena and mechanistic evidence emerging from studies of stress-induced phenoptosis in the multicellular organism C. elegans and stress-induced deaths at cellular levels in organisms ranging from bacteria to mammals, focusing on abiotic and pathogen stresses. Genes and signaling pathways involved in phenoptosis appear to promote organismic death during severe stress and aging, while conferring fitness and immune defense during mild stress and early life, consistent with their antagonistic pleiotropy actions. As cell apoptosis during development can shape tissues and organs, stress-induced phenoptosis may also contribute to possible benefits at the population level, through mechanisms including kin selection, abortive infection, and soma-to-germline resource allocation. Current models can generate experimentally testable predictions and conceptual frameworks with implications for understanding both stress-induced phenoptosis and natural aging.
