In potential breakthrough research, experts are measuring cell and tissue decline to better understand how we age and to make better aging therapeutics.
Published by Brett J. Weiss 2 April 2021
How do we define aging? Historically, we’ve counted the number of times we live while the Earth orbits the sun (chronological age in years), but nowadays we can also think about the accumulation of cell and tissue damage (biological age). Right now, the aging research field is having a “eureka” moment — we’re rapidly uncovering how and why we age and potential aging therapeutic options. What we’re starting to see is that the topic of biological aging is a key to understanding the aging process and may provide a means to achieve milestone, aging-related discoveries.
Getting at the heart of crucial biological concepts will help us understand what researchers are doing in this defining moment in the study of aging. These topics range from the level of DNA molecules and chromosomes to cells and tissues of the body.
Aging researchers have proposed that DNA damage that causes chromosome instability — where chromosomes lose structural integrity — is a primary cause of aging, affecting the quality of our cells’ molecular machines (proteins) that the DNA codes for. The underlying accumulation of DNA mutations, a concept referred to as “mutational load”, extensively contributes to chromosome instability. The idea is that with passing years, spontaneous, deleterious DNA mutations build-up resulting in “mutational load.” Although the aging effects of these mutations remain murky, such as how they alter proteins, DNA mutations seem to correlate with aging in tissues like skeletal muscle.
Another hot topic in biological aging research is chromosome end length. Scientists refer to these chromosome ends as “telomeres”, which appear to decay with age. What we’re finding is that the enzymes that facilitate their repair (telomerase) can’t keep up with their fraying and decay as aging progresses. So, researchers have sought ways to measure biological age by looking at chromosome end health, however, how telomere length affects aging remains unclear.
Another growing aging research concept is about cellular aging or “senescence.” When cells become senescent, that means they’ve reached an age-related, non-proliferating state. Researchers are still trying to figure out how senescence gets initiated. Interestingly, one way that cells become senescent appears to be linked to telomere shortening. Overall, quantifying senescent cell accumulation and burden on the body may provide an informative way to track biological aging. In fact, this method to measure biological aging may soon enter clinical research and medical practice, providing hope in elucidating the processes underlying aging.
Another way to measure aging is based on epigenetics, which is based on the accumulation of molecules that ornament our DNA called “methyl groups.” Studies show that “epigenetically older” individuals with more DNA methyl groups have a higher risk for developing age-related diseases. So, to measure biological age epigenetically and determine age-related disease risk, researchers have developed tools to measure and analyze accumulating patterns of DNA methyl groups. These techniques measuring biological age can help to determine what variables play into how fast passing years take a toll on the body and may also lead to methods to possibly even reverse biological age by manipulating patterns of DNA methyl groups.
The mitochondria, commonly referred to as the cell’s powerhouse, can also provide a way to measure biological aging. Mitochondria exist throughout the body, as cells need them to generate energy. As we age, mitochondria lose their ability to generate energy, which can lead to fatigue and age-related metabolic disorders. Research has shown that taking supplements called NAD+ precursors, such as nicotinamide mononucleotide (NMN), can boost mitochondrial production and function with possible effects on increasing energy levels and preventing age-related diseases.
The health of our blood vessels, or vascular health, can serve as biological indicators (biomarkers) that predict the occurrence of death (mortality). By applying what we know about blood vessel health and mortality risk, we can get a better idea of how fast people age.
These biomarker indicators of blood vessel health include measures of blood pressure and altered blood flow through vessels as well as blood vessel stiffness and the accumulation of plaque and calcium (calcification). Other blood vessel markers of aging not related to vessel structure and function include DNA mutations, markers of inflammation called interleukins, and protein-based indicators of blood vessel dysfunction. Perhaps in the future, by looking at these blood vessel biomarkers in younger adults, we can prevent age-related diseases and optimize solid health-related choices that improve each individual’s longevity.
From using methods to measure biological aging to finding ways to prevent and mitigate age-related diseases, biological aging research is in its heyday for helping scientists who study aging make discoveries. Not only will measuring biological age help with predicting age-related diseases, but it can also help us study how people age and what factors contribute to their aging. New molecules, like NMN and other popular NAD+ precursors, can also help us to minimize the damage from aging and prevent age-related deteriorating health. Combinations of NAD+-boosting molecules along with other anti-aging compounds may pave the way to lifespan extension therapies in the future. In due time, it’s probable that research will continue to provide insight to help us get a better handle on biological aging to improve our quality of life and help us live longer. Treating aging itself could also lead to breakthrough discoveries in age-related disease treatments for ailments like cancer, stroke, diabetes, and Alzheimer’s disease.
Researchers fight off childhood neurodegenerative disease characteristics rooted in NAD+ deficiency, mitochondrial damage, and senescence
Published by Jonathan D. Grinstein, Ph.D. 12 April 2021
· Mitochondrial dysfunction drives premature aging seen in ataxia telangiectasia (A-T).
· Enhancing mitochondrial recycling by boosting NAD+ is a potential therapeutic intervention for (A-T).
Ataxia telangiectasia (A-T) is a devastating, complex genetic disorder characterized by degeneration of the nervous system often during infancy or early childhood. Premature aging diseases like A-T are often linked to breakdown and leakage of the battery packs that generate energy for our cells (mitochondria) and senescence — an arrest in cell growth and replication that’s necessary to keep our organs from decaying. These phenomena happen in natural aging too, but don’t take off so early in life and at such a rapid rate. But whether cells freeze up and mitochondria crash hasn’t been explored regarding A-T.
In an article published in Aging Cell, Yang and colleagues from the National Institute on Aging demonstrate that the buildup of damaged mitochondria and senescent cells occurs in cells from A-T patient as well as cultured human cells and mice that model the disease. The research team based out of Bethesda, Maryland, find that boosting levels of nicotinamide adenine dinucleotide (NAD+) — a molecule at the core of many processes, including mitochondrial function and recycling — clears damaged mitochondria and prevents senescence in A-T models.
These findings link the neurological symptoms of A-T directly to senescence and the loss of healthy mitochondrial populations within cells.
“Our data support the concept that targeting the maintenance of mitochondrial quality may have potential roles in the prevention of senescence and neuroinflammation in neurodegenerative diseases,” concluded Yang and colleagues.
In humans, loss of a particular molecular machine (enzyme) results in A-T, a rare inherited genetic disease characterized by neurodegeneration as well as cancer predisposition, sterility, and immune deficiency. A-T patients also suffer from a variety of inflammatory characteristics, which are thought to be rooted in the failed development of certain immune cells.
The enzyme ATM kinase, which is encoded by the ataxia telangiectasia-mutated (ATM) gene, is a master regulator of the DNA repair responses. When DNA gets damaged, ATM gets activated. While some major features of A-T reflect inefficient DNA repair, how this all translates into neurodegeneration in A-T is poorly understood.
There are clues that unresolved DNA damage can impair mitochondrial function, promote disease development, and accelerate aging, as reported in A-T. One clue about the inner workings of A-T may lie in the growing evidence that persistent DNA damage and senescence are linked.
Another driver of age-related decline is the loss of mitochondrial function. Multiple lines of evidence point to mitochondrial dysfunction as a component of A-T features. Dysfunctional mitochondria can induce senescence in cultured cells and animals. Driving mitochondrial function is a molecule called NAD+, which is deficient in ATM-deficient neurons. But, little is known about the connections between senescence, inflammation of the nervous system, mitochondrial dysfunction, and NAD+.
In this study, Yang and colleagues looked at whether mitochondrial dysfunction and senescence were at play in cells from A-T patients as well as ATM-deficient neural cells and mice. They found that cells from A-T patients and those lacking ATM have impaired mitophagy — the process of clearing damaged mitochondria — and consequently promotes the release of mitochondrial DNA into the cytoplasm. This build up of cytoplasmic DNA triggers an antiviral immune response in the brain called STING, which initiates a robust pro-inflammatory response and senescence linked to the deficient health span in ATM-deficient mice.
Yang and colleagues went on to show that the accumulation of fragmented DNA floating around in the cytoplasm dropped by boosting the cell levels of NAD+. They think that the NAD+ boosting works by activating mitophagy because the NAD+ precursor nicotinamide riboside (NR) failed to prevent senescence following inhibition of mitophagy.
The National Institute on Aging research team also found that the effects of enhancing NAD+ levels affected not only ATM-deficient cells but also at the level of behavior. In mice lacking ATM, NR prevented neuroinflammation and senescence through enhancing mitochondrial function, reducing cytoplasmic DNA and preventing activation of STING in ATM-deficient cells and mice. ATM-deficient mice also regained motor function when their NAD+ levels were restored.
As NAD+ plays important roles in a multitude of molecular and cell processes, including DNA repair, mitochondrial function, and senescence, supplementation of NAD+ is critical and beneficial in settings like A-T or normal aging where NAD+ levels are low. But whether elevating NAD+ levels can prevent aging in humans remains to be determined. Studies are needed to test whether this is applicable in A-T patients and other premature aging conditions prior to be made available in a clinical setting.
Increasing production of SIRT6 extends lifespan by about 20%, improves physical activity, and mitigates frailty in old age.
Published by By Brett J. Weiss 8 June 2021.
· Mice genetically modified to overproduce SIRT6 protein see drastic increases in lifespan and physical performance.
· SIRT6 improves liver cell energy and glucose sugar production for improved physical activity, healthspan, and survival.
The rising aging global population, referred to as the “Silver Wave,” presents health-related challenges that include age-related diseases and frailty – a condition characterized by fatigue and weakness. Research shows that diet and metabolism are key regulators of lifespan, representing targetable intervention strategies to promote healthy aging. Scientists have uncovered that a protein called SIRT6 regulates aging, obesity, and insulin sensitivity, but how it does so needs further clarification to improve our attempts to maintain and preserve health during aging.
Cohen and colleagues from Bar-Ilan University in Israel published a study in Nature Communications showing that driving SIRT6 protein production extends mouse lifespan by about 20%. They also show that enhancing SIRT6 production through genetic manipulation in older ages optimizes the energy production balance (homeostasis) of liver and fat tissues to delay frailty and extend life without disease (healthspan).
“This discovery, combined with our previous findings, shows that SIRT6 controls the rate of healthy aging,” said Professor Cohen in a press release. “If we can determine how to activate it in humans, we will be able to prolong life, and this could have enormous health and economic implications.”
Sirtuins are proteins that require the essential, life-sustaining molecule called nicotinamide adenine dinucleotide (NAD+) to perform their function. When sirtuins have enough NAD+ to work properly, they play crucial roles in maintaining DNA health and cell metabolism. Two of the seven sirtuins, SIRT1 and SIRT6, have been suspected of regulating metabolism and aging processes, leading Cohen and colleagues to tease out which of these two sirtuins is most important during aging or whether they act synergistically.
To explore the interaction between SIRT1 and SIRT6 in aging and lifespan, the Israel-based research team genetically modified mice to produce more SIRT1 (SIRT1 transgenic mice), more SIRT6 (SIRT6 transgenic mice), or both (SIRT1 + SIRT6 transgenic mice). They followed the groups of mice for up to 40 months to compare their lifespans. They found that the male and female SIRT6 transgenic mice lived, on average, about 27% and 15% longer than non-modified mice and SIRT1 transgenic mice, respectively. There was no significant difference in lifespan between SIRT6 transgenic and SIRT1 + SIRT6 transgenic mice, so Cohen and colleagues concluded the two proteins don’t synergistically extend lifespan but that SIRT 6 overproduction does so on its own.
To see if the increased SIRT6 protein levels provide healthspan benefits, Cohen and colleagues compared the distances that the three groups of older transgenic mice ran on a spinning wheel, which is indicative of physical performance. Greater distances run indicate reduced frailty since fatigued and tired older mice prefer to remain stationary. The research group found that older, 15-month-old SIRT6 and SIRT1 + SIRT6 but not SIRT1 transgenic mice ran greater distances during nighttime hours, when mice are most active. Because increased SIRT6 protein levels were present in the mouse groups running longer distances but elevated SIRT1 levels alone didn’t yield these results, Cohen and colleagues determined higher SIRT6 levels drive the reduced frailty in older-aged mice.
After determining that increasing SIRT6 protein levels substantially extends mouse health and lifespan, Cohen and colleagues wanted to figure out what physiological mechanisms explain these benefits. By measuring the activity of genes and protein levels involved in energy production, Cohen and colleagues found that SIRT6 preserves metabolism pathways that use NAD+ in old age. Their research indicates that metabolic pathways in the liver producing energy (ATP) along with the sugar glucose deteriorate during aging, leading to perturbed energy homeostasis. Increasing SIRT6 levels in the liver as mice get older enhances energy production and preserves ATP levels along with glucose for brain function.
By significantly increasing cell energy and glucose production, SIRT6 stimulates the physiological response that is identical to intermittent fasting, a reduced-calorie diet that increases longevity. Cohen’s laboratory is currently trying to devise ways to extend healthy life based on these findings.
For the first time, a clinical study in older men shows that taking NMN increases blood NAD+ levels and improves various indicators of muscle strength and performance.
This is an article published on https://www.nmn.com/news/12-weeks-of-nmn-supplementation-improves-muscle-function. By Brett J. Weiss 18 June 2021.
NMN raises blood NAD+ and NAD+ metabolite levels in men over 65.
Supplementing with 250 mg of NMN for 12-weeks enhances muscle function and mobility.
Animal studies have shown that administering the precursor molecule nicotinamide mononucleotide (NMN) elevates nicotinamide adenine dinucleotide (NAD+) levels. Interestingly, age-related NAD+ level reductions have been linked to cardiovascular, neurodegenerative, and metabolic diseases along with reduced muscle function, which NMN supplementation ameliorates – at least in rodents. So, how can we figure out whether NMN supplementation helps with these age-related conditions in humans?
Yamauchi and colleagues from the University of Tokyo released a non-peer reviewed journal article in Research Square showing that orally treating men over age 65 with 250 mg per day of NMN significantly increased their NAD+ levels and improved their muscle performance. Specifically, supplementing with NMN increased the number of times they rose from a chair in 30 seconds, enhanced walking speed, and improved grip strength. Findings from the study add more evidence that NMN’s healthy aging benefits seen in animals like rodents translate to humans.
“We report that supplementation of 250 mg/d NMN for 12 weeks in healthy old men was safe, well tolerated, and significantly increased NAD+ and NAD+ metabolites in whole blood,” said Yamauchi and colleagues. “Additionally, NMN induced improvements in muscle strength and performance. Thus, chronic oral administration of NMN could be an effective strategy for the prevention of age-related muscle disorders.”
Taking NMN for 12-weeks is Well-Tolerated
Before Yamauchi and colleagues tested how effective NMN is at improving muscle function in aged men, the research team wanted to know whether taking it is safe. The research team looked at common blood chemistry measurements indicative of toxicity that included liver enzymes and markers of kidney function after 12 weeks of daily NMN usage. Importantly, the lab results were unaltered in the group of men who took NMN compared to those that did not, indicating that taking NMN is well-tolerated.
Oral NMN Increases NAD+ Levels in People
Since previous research has shown that NMN supplementation increases blood NAD+ levels in aged rodents and that these higher NAD+ levels correlate with improved disease conditions, Yamauchi and colleagues tested whether NMN supplementation increases NAD+ in aged men. They found that the 12-week NMN supplementation substantially increased blood NAD+ levels, providing the first results from any study showing that NMN increases blood NAD+ in humans.
“This is the first study to report that NMN administration significantly increased NAD+ and NAD+ metabolites in the whole blood,” said Yamauchi and colleagues.
Further analyses demonstrated that NMN supplementation improves NAD+ metabolism by promoting NMN’s conversion to NAD+ and the conversion of other NMN metabolites to NAD+ through a separate NAD+ synthesis pathway (the de novo pathway). These findings open up the possibility that NMN drives NAD+ production by activating more than one NAD+ biosynthesis pathway.
Taking NMN substantially increases blood NMN and NAD+ levels. Following 12 weeks of daily NMN supplementation, blood NMN levels were significantly higher (A), and NAD+ levels were substantially higher (B). These findings are the first to show that long-term NMN administration increases blood NAD+ levels in people.
NMN Enhances Muscle Performance in Men Age 65 and Older
To find out whether these NMN-induced NAD+ level elevations drive improved physical function, Yamauchi and colleagues tested muscle strength and performance. They found that NMN significantly improved several indicators of muscle strength and performance: walking speed, grip strength, and the number of times the participants could stand up from a chair in 30 seconds. Their results demonstrate that oral NMN supplementation for 12 weeks improves muscle strength and performance in healthy, older men.
Taking NMN daily for 12 weeks significantly improves walking speed, grip strength, and the number of times rising from a chair in 30 seconds. Walking speed (gait speed) in meters per second substantially increased as shown in the upper left quadrant. The lower left quadrant shows that the number of times rising from a chair in 30 seconds (a 30-second chair-stand test) increased significantly after six weeks with NMN supplementation. Left hand grip strength shown in the lower right quadrant also increased significantly with NMN supplementation. These findings indicate that NMN improves muscle motility and function.
“We reported that the chronic oral supplementation of 250 mg NMN per day is safe and a well-tolerated and effective strategy for boosting NAD+ metabolism in healthy elderly men,” stated Yamauchi and colleagues. “Additionally, our exploratory analyses of the effects of NMN supplementation on physiological functions suggest the ability of NMN to improve muscle strength, which is an important clinical indicator of aging.”
How Does NMN Improve Muscle Function?
Although these findings point to long-term NMN supplementation promoting overall muscle health, there’s no evidence as to how this all works. What’s more, the study was performed in a small group of healthy older men. To be more certain of the main conclusions that NMN can boost NAD+ levels and improve muscle strength and performance in people, these studies need to be replicated in a larger group of adults that also includes women. Nevertheless, this is a step in the right direction for NMN to be considered a clinically proven anti-aging agent, as this study is a promising indicator that some of the anti-aging effects of NMN seen in rodents may extend to humans.
What’s more, the 250 mg per day dosage used has been applied in another study showing that NMN improves muscle insulin sensitivity in older women. So, 250 mg per day may give an effective dose in older people, but a study in Japanese men showed that up to 500 mg is well-tolerated. The question, therefore, remains as to whether further benefits could be seen with higher doses that are safely tolerated.
Published: July 2020
Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Currently, there are no treatments for dry AMD, which is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors.
Reports from human donors with AMD suggest that RPE mitochondrial defects are a key event in AMD pathology. Thus, the most eﬀective strategy for treating dry AMD is to identify compounds that enhance mitochondrial function and subsequently, preserve the RPE.
In this study, primary cultures of RPE from human donors with (n = 20) or without (n = 8) AMD were used to evaluate compounds that are designed to
Mitochondrial function measured after drug treatments showed an AMDdependent response; only RPE from donors with AMD showed improvements.
All four drugs caused a signiﬁcant increase in maximal respiration (p < 0.05) compared to untreated controls. Treatment with Rapamycin, PQQ, or NMN signiﬁcantly increased ATP production (p < 0.05). Only Rapamycin increased basal respiration (p < 0.05).
Notably, robust responses were observed in only about 50% of AMD donors, with attenuated responses observed in the remaining AMD donors.
Further, within the responders, individual donors exhibited a distinct reaction to each drug.
Our results suggest drugs targeting pathways involved in maintaining healthy mitochondria can improve mitochondrial function in a select population of RPE from AMD donors.
The unique response of individual donors to speciﬁc drugs supports the need for personalized medicine when treating AMD.
Published: July 2020
Hypoglycemia-induced brain injury is a potential complication of insulin therapy in diabetic patients. Severe hypoglycemia triggers a cascade of events in vulnerable neurons that may lead to neuronal death and cognitive impairment even after glucose normalization. Oxidative stress and the activation of poly (ADP-ribose) polymerase-1 (PARP-1) are key events in this cascade.
The production of reactive oxygen species (ROS) induces DNA damage and the consequent PARP-1 activation, which depletes NAD+ and ATP, resulting in brain injury. One of the key precursors of NAD+ is nicotinamide mononucleotide (NMN), which is converted to NAD+ and reduces production of ROS. Here we investigated whether NMN could reduce brain injury after severe hypoglycemia.
We used a rat model of insulin-induced severe hypoglycemia and injected NMN (500 mmg/kg, i.p., one week) following 30 min of severe hypoglycemia, at the time of glucose administration. One week after severe hypoglycemia, hippocampal long-term potentiation (LTP), an electrophysiogic assay of synaptic plasticity, was examined and neuronal damage was assessed by Hematoxylin-Eosin staining. ROS accumulation, PARP-1 activation, NAD+ and ATP levels in hippocampus were also measured.
Cognitive function was assessed using the Morris water maze 6 weeks after severe hypoglycemia. The addition of NMN reduced neuron death by 83 ± 3% (P < 0.05) after severe hypoglycemia. The hippocampal LTP was significantly reduced by severe hypoglycemia but showed recovery in the NMN addition group. NMN treatment also attenuated the severe hypoglycemia-induced spatial learning and memory impairment.
Mechanically, we showed that NMN administration decreased ROS accumulation, suppressed PARP-1 activation, and restored levels of NAD+ and ATP in hippocampus. All these protective effects were reversed by 3-acetylpyridine (3-AP), which generates inactive NAD+.
In summary, NMN administration following severe hypoglycemia could ameliorate neuronal damage and cognitive impairment caused by severe hypoglycemia. These results suggest that NMN may be a promising therapeutic drug to prevent hypoglycemia-induced brain injury.