The coupling of nicotinamide adenine dinucleotide (NAD+) breakdown and protein deacylation is a unique feature of the family of proteins called ‘sirtuins.’ This intimate connection between NAD+ and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms.
Although the field of sirtuin research went through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an evolutionarily conserved aging/longevity regulator. The tight connection between NAD+ and sirtuins is regulated at several different levels, adding further complexity to their coordination in metabolic and aging/longevity control.
Interestingly, it has been demonstrated that NAD+ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level. These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and the pathogenesis of diseases of aging.
To mitigate these age-associated problems, supplementation of key NAD+ intermediates is currently drawing significant attention. In this review article, we will summarize these important aspects of the intimate connection between NAD+ and sirtuins in aging/longevity control.
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.
Older men (n = 12) and women (n = 18) 65–80 years of age completed twelve weeks of exercise and took either a placebo or resveratrol (500 mg/day) to test the hypothesis that resveratrol treatment combined with exercise would increase mitochondrial density, muscle fatigue resistance, and cardiovascular function more than exercise alone.
Contrary to our hypothesis, aerobic and resistance exercise coupled with resveratrol treatment did not reduce cardiovascular risk further than exercise alone. However, exercise added to resveratrol treatment improved the indices of mitochondrial density, and muscle fatigue resistance, more than placebo and exercise treatments.
In addition, subjects that were treated with resveratrol had an increase in knee extensor muscle peak torque (8%), average peak torque (14%), and power (14%) after training, whereas exercise did not increase these parameters in the placebo-treated older subjects. Furthermore, exercise combined with resveratrol significantly improved mean fiber area and total myonuclei by 45.3% and 20%, respectively, in muscle fibers from the vastus lateralis of older subjects.
Together, these data indicate a novel anabolic role of resveratrol in exercise-induced adaptations of older persons and this suggests that resveratrol combined with exercise might provide a better approach for reversing sarcopenia than exercise alone.
NAD+ is a redox-active metabolite, the depletion of which has been proposed to promote aging and degenerative diseases in rodents. However, whether NAD+ depletion occurs in patients with degenerative disorders and whether NAD+ repletion improves their symptoms has remained open.
Here, we report systemic NAD+ deficiency in adult-onset mitochondrial myopathy patients. We administered an increasing dose of NAD+-booster niacin, a vitamin B3 form (to 750-1,000 mg/day; clinicaltrials.gov NCT03973203) for patients and their matched controls for 10 or 4 months, respectively.
Blood NAD+ increased in all subjects, up to 8-fold, and muscle NAD+ of patients reached the level of their controls. Some patients showed anemia tendency, while muscle strength and mitochondrial biogenesis increased in all subjects. In patients, muscle metabolome shifted toward controls and liver fat decreased even 50%.
Our evidence indicates that blood analysis is useful in identifying NAD+ deficiency and points niacin to be an efficient NAD+ booster for treating mitochondrial myopathy.
Scientific and technological progress might change people’s capabilities or incentives in ways that would destabilize civilization. For example, advances in DIY biohacking tools might make it easy for anybody with basic training in biology to kill millions; novel military technologies could trigger arms races in which whoever strikes first has a decisive advantage; or some economically advantageous process may be invented that produces disastrous negative global externalities that are hard to regulate.
This paper introduces the concept of a vulnerable world : roughly, one in which there is some level of technological development at which civilization almost certainly gets devastated by default, i.e. unless it has exited the ‘semi‐anarchic default condition’.
Several counterfactual historical and speculative future vulnerabilities are analyzed and arranged into a typology. A general ability to stabilize a vulnerable world would require greatly amplified capacities for preventive policing and global governance.
The vulnerable world hypothesis thus offers a new perspective from which to evaluate the risk‐benefit balance of developments towards ubiquitous surveillance or a unipolar world order.
Longer human lives have led to a global burden of late-life disease. However, some older people experience little ill health, a trait that should be extended to the general population.
Interventions into lifestyle, including increased exercise and reduction in food intake and obesity, can help to maintain healthspan. Altered gut microbiota, removal of senescent cells, blood factors obtained from young individuals and drugs can all improve late-life health in animals.
Application to humans will require better biomarkers of disease risk and responses to interventions, closer alignment of work in animals and humans, and increased use of electronic health records, biobank resources and cohort studies.
Inhibitors of mTOR, including clinically available rapalogs such as rapamycin (Sirolimus) and Everolimus, are gerosuppressants, which suppress cellular senescence. Rapamycin slows aging and extends life span in a variety of species from worm to mammals. Rapalogs can prevent age-related diseases, including cancer, atherosclerosis, obesity, neurodegeneration and retinopathy and potentially rejuvenate stem cells, immunity and metabolism.
[In this paper] I further suggest how rapamycin can be combined with metformin, inhibitors of angiotensin II signaling (Losartan, Lisinopril), statins (simvastatin, atorvastatin), propranolol, aspirin and a PDE5 inhibitor. Rational combinations of these drugs with physical exercise and an anti-aging diet (Koschei formula) can maximize their anti-aging effects and decrease side effects.
Sirtuin is an essential factor that delays cellular senescence and extends the organismal lifespan through the regulation of diverse cellular processes. Suppression of cellular senescence by sirtuin is mainly mediated through delaying the age-related telomere attrition, sustaining genome integrity and promotion of DNA damage repair.
In addition, sirtuin modulates the organismal lifespan by interacting with several lifespan regulating signaling pathways including insulin/IGF-1 signaling pathway, AMP-activated protein kinase, and forkhead box O. Although still controversial, it is suggested that the prolongevity effect of sirtuin is dependent with the level of and with the tissue expression of sirtuin. Since sirtuin is also believed to mediate the prolongevity effect of calorie restriction, activators of sirtuin have attracted the attention of researchers to develop therapeutics for age-related diseases.
Resveratrol, a phytochemical rich in the skin of red grapes and wine, has been actively investigated to activate sirtuin activity with consequent beneficial effects on aging. This article reviews the evidences and controversies regarding the roles of sirtuin on cellular senescence and lifespan extension, and summarizes the activators of sirtuin including sirtuin-activating compounds and compounds that increase the cellular level of nicotinamide dinucleotide (NAD).
Age is the primary risk factor for the vast majority of disorders, including neurodegenerative diseases impacting brain function. Whether the consequences of aging at the biological level can be reversed, or age-related changes prevented, to change the trajectory of such disorders is thus of extreme interest and value.
Studies using young plasma, the acellular component of blood, have demonstrated that aging is malleable, with the ability to restore functions in old animals. Fascinatingly, this functional improvement is even observed in the brain, despite the blood-brain barrier, indicating that peripheral sources can effectively impact central sites leading to clinically relevant changes such as enhancement of cognitive function.
A plasma-based approach is also attractive as aging is inherently complex, with an array of mechanisms dysregulated in diverse cells and organs throughout the body leading to disturbed function. Plasma, containing a natural mixture of components, has the ability to act multimodally, modulating diverse mechanisms that can converge to change the trajectory of age-related diseases.
Here we review the evidence that plasma modulates aging processes in the brain and consider the therapeutic applications that derive from these observations. Plasma and plasma-derived therapeutics are an attractive translation of this concept, requiring critical consideration of benefits, risks, and ethics. Ultimately, knowledge derived from this science will drive a comprehensive molecular understanding to deliver optimized therapeutics. The potential of highly differentiated, multimodal therapeutics for treatment of age-related brain disorders provides an exciting new clinical approach to address the complex etiology of aging.
Background: Synucleinopathies of the aging population are a heterogeneous group of neurological disorders that includes Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and are characterized by the progressive accumulation of α-synuclein in neuronal and glial cells.
Toll-like receptor 2 (TLR2), a pattern recognition immune receptor, has been implicated in the pathogenesis of synucleinopathies because TLR2 is elevated in the brains of patients with PD and TLR2 is a mediator of the neurotoxic and pro-inflammatory effects of extracellular α-synuclein aggregates. Therefore, blocking TLR2 might alleviate α-synuclein pathological and functional effects. For this purpose, herein, we targeted TLR2 using a functional inhibitory antibody (anti-TLR2).
Methods: Two different human α-synuclein overexpressing transgenic mice were used in this study. α-synuclein low expresser mouse (α-syn-tg, under the PDGFβ promoter, D line) was stereotaxically injected with TLR2 overexpressing lentivirus to demonstrate that increment of TLR2 expression triggers neurotoxicity and neuroinflammation. α-synuclein high expresser mouse (α-Syn-tg; under mThy1 promoter, Line 61) was administrated with anti-TLR2 to examine that functional inhibition of TLR2 ameliorates neuropathology and behavioral defect in the synucleinopathy animal model. In vitro α-synuclein transmission live cell monitoring system was used to evaluate the role of TLR2 in α-synuclein cell-to-cell transmission.
Results: We demonstrated that administration of anti-TLR2 alleviated α-synuclein accumulation in neuronal and astroglial cells, neuroinflammation, neurodegeneration, and behavioral deficits in an α-synuclein tg mouse model of PD/DLB. Moreover, in vitro studies with neuronal and astroglial cells showed that the neuroprotective effects of anti-TLR2 antibody were mediated by blocking the neuron-to-neuron and neuron-to-astrocyte α-synuclein transmission which otherwise promotes NFκB dependent pro-inflammatory responses.
Conclusion: This study proposes TLR2 immunotherapy as a novel therapeutic strategy for synucleinopathies of the aging population.
EDITOR’S NOTE: antibodies against TLR2 are injected into the mouse; the antibodies bind to the toll-like receptors, and α-synuclein can no longer pass from neuron to neuron. The α-synuclein doesn’t accumulate, the neurons are not inflamed, the brain does not degenerate, the mouse acts normally.
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