Long-term caloric restriction


Objectives: We determined whether caloric restriction (CR) has cardiac-specific effects that attenuate the established aging-associated impairments in diastolic function.

Background: Caloric restriction retards the aging process in small mammals; however, no information is available on the effects of long-term CR on human aging. In healthy individuals, Doppler echocardiography has established the pattern of aging-associated diastolic impairment, whereas little change is observed in systolic function.

Methods: Diastolic function was assessed in 25 subjects (age 53 +/- 12 years) practicing CR for 6.5 +/- 4.6 years and 25 age- and gender-matched control subjects consuming Western diets. Diastolic function was quantified by transmitral flow, Doppler tissue imaging, and model-based image processing (MBIP) of E waves. C-reactive protein (CRP), TNF-alpha and TGF-beta1 were also measured.

Results: No difference in systolic function was observed between groups; however, standard transmitral Doppler flow diastolic function indexes of the CR group were similar to those of younger individuals, and MBIP-based, flow-derived diastolic function indexes, reflecting chamber viscoelasticity and stiffness, were significantly lower than in control subjects.

Blood pressure, serum CRP, TNF-alpha, and TGF-beta1 levels were significantly lower in the CR group (102 +/- 10/61 +/- 7 mm Hg, 0.3 +/- 0.3 mg/l, 0.8 +/- 0.5 pg/ml, 29.4 +/- 6.9 ng/ml, respectively) compared with the Western diet group (131 +/- 11/83 +/- 6 mm Hg, 1.9 +/- 2.8 mg/l, 1.5 +/- 1.0 pg/ml, 35.4 +/- 7.1 ng/ml, respectively).

Conclusions: Caloric restriction has cardiac-specific effects that ameliorate aging-associated changes in diastolic function. These beneficial effects on cardiac function might be mediated by the effect of caloric restriction on blood pressure, systemic inflammation, and myocardial fibrosis.

SOURCE: J Am Coll Cardiol

EDITOR’S NOTE: The middle-aged adults in the calorie restriction group maintained an average blood pressure (102/61) that in Western society is normally characteristic of a pre-teen.

From rapalogs to anti-aging formula


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.

SOURCE: Oncotarget

Reversing (cellular) aging


Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis.

Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells.

Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.

EDITOR’S NOTE: brief exposure to Yamakana factors (proteins that are used to convert cells to stem cells) somehow reversed many of the epigenetic changes (errors) that accumulate with age, making ‘old’ cells ‘young’ again.

Human gut microbiome aging clock


The human gut microbiome is a complex ecosystem that both affects and is affected by its host status. Previous metagenomic analyses of gut microflora revealed associations between specific microbes and host age. Nonetheless there was no reliable way to tell a host’s age based on the gut community composition.

Here we developed a method of predicting hosts’ age based on microflora taxonomic profiles using a cross-study dataset and deep learning. Our best model has an architecture of a deep neural network that achieves the mean absolute error of 5.91 years when tested on external data. We further advance a procedure for inferring the role of particular microbes during human aging and defining them as potential aging biomarkers.

The described intestinal clock represents a unique quantitative model of gut microflora aging and provides a starting point for building host aging and gut community succession into a single narrative.

FULL TEXT (PDF): iScience

Boosting NAD+ improves muscle disease


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.

SOURCE: Cell Metabolism

EDITOR’S NOTE: Increased blood levels of NAD+ were achieved here with a readily available supplement, niacin (vitamin B3).

Intermittent fasting dawn-to-dusk


Murine studies showed that disruption of circadian clock rhythmicity could lead to cancer and metabolic syndrome. Time-restricted feeding can reset the disrupted clock rhythm, protect against cancer and metabolic syndrome. Based on these observations, we hypothesized that intermittent fasting for several consecutive days without calorie restriction in humans would induce an anticarcinogenic proteome and the key regulatory proteins of glucose and lipid metabolism.

Fourteen healthy subjects fasted from dawn to sunset for over 14 h daily. Fasting duration was 30 consecutive days. Serum samples were collected before 30-day intermittent fasting, at the end of 4th week during 30-day intermittent fasting, and one week after 30-day intermittent fasting. An untargeted serum proteomic profiling was performed using ultra high-performance liquid chromatography / tandem mass spectrometry.

Our results showed that 30-day intermittent fasting was associated with an anticancer serum proteomic signature, upregulated key regulatory proteins of glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system, and cognitive function, and resulted in a serum proteome protective against cancer, metabolic syndrome, inflammation, Alzheimer’s disease, and several neuropsychiatric disorders.

These findings suggest that fasting from dawn to sunset for 30 consecutive days can be preventive and adjunct therapy in cancer, metabolic syndrome, and several cognitive and neuropsychiatric diseases.

MANUSCRIPT: Journal of Proteomics

An acetylation switch of the NLRP3 inflammasome


It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges upon the diabetes pandemic is largely unknown.

Here, we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD +-dependent deacetylase and a metabolic sensor.

We have developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models; and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance.

These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlight the reversibility of aging-associated chronic inflammation and insulin resistance.

FULL TEXT: Cell Metabolism

EDITOR’S NOTE: the deacetylation step, performed by SIRT2, is switched ‘on’ in healthy cells. This is one more part of the NAD+ / sirtuin puzzle. The goal is to keep NAD+ and sirtuins functioning normally.