Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression
M H Milekic, Y Xin, A O’Donnell, K K Kumar, M Bradley-Moore, D Malaspina, H Moore, D Brunner, Y Ge, J Edwards, S Paul, F G Haghighi and J A Gingrich
Advanced paternal age (APA) has been shown to be a significant risk factor in the offspring for neurodevelopmental psychiatric disorders, such as schizophrenia and autism spectrum disorders. During aging, de novo mutations accumulate in the male germline and are frequently transmitted to the offspring with deleterious effects. In addition, DNA methylation during spermatogenesis is an active process, which is susceptible to errors that can be propagated to subsequent generations. Here we test the hypothesis that the integrity of germline DNA methylation is compromised during the aging process. A genome-wide DNA methylation screen comparing sperm from young and old mice revealed a significant loss of methylation in the older mice in regions associated with transcriptional regulation. The offspring of older fathers had reduced exploratory and startle behaviors and exhibited similar brain DNA methylation abnormalities as observed in the paternal sperm. Offspring from old fathers also had transcriptional dysregulation of developmental genes implicated in autism and schizophrenia. Our findings demonstrate that DNA methylation abnormalities arising in the sperm of old fathers are a plausible mechanism to explain some of the risks that APA poses to resulting offspring.
Paternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity
Brian M. D’Onofrio, PhD1; Martin E. Rickert, PhD1; Emma Frans, MSc2; Ralf Kuja-Halkola, MSc2; Catarina Almqvist, MD2,3; Arvid Sjölander, PhD2; Henrik Larsson, PhD2; Paul Lichtenstein, PhD2
[+] Author Affiliations
JAMA Psychiatry. 2014;71(4):432-438. doi:10.1001/jamapsychiatry.2013.4525.
Text Size: A A A
ABSTRACT | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | REFERENCES
Importance Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors.
Objective To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity.
Design, Setting, and Participants We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2 615 081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins.
Exposure Paternal age at childbearing.
Main Outcomes and Measures Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity.
Results In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings.
Conclusions and Relevance Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.
By Dr. Mercola
Provocative new research involving data from nearly 3 million adults suggests that a having an overweight body mass index (BMI) may be linked to a longer life than one that puts you within a “normal” weight range.
The research, which analyzed 97 studies in all, found that people with BMIs under 30 but above normal (the overweight range) had a 6 percent lower risk of dying from all causes than those who were normal weight, while those whose BMIs fell into the obese range were 18 percent more likely to die of any cause.1 The researchers wrote:
“Relative to normal weight … overweight was associated with significantly lower all-cause mortality.”
Do a Few Extra Pounds Make You Healthier?
The study results imply, at least superficially, that carrying some extra weight may help you live longer … or at the very least may not be as unhealthy as it’s made out to be. In a JAMA editorial, Steven Heymsfield, M.D. and William Cefalu, M.D. highlighted this notion:2
“The presence of a wasting disease, heart disease, diabetes, renal dialysis, or older age are all associated with an inverse relationship between BMI and mortality rate, an observation termed the obesity paradox or reverse epidemiology.
The optimal BMI linked with lowest mortality in patients with chronic disease may be within the overweight and obesity range.
Even in the absence of chronic disease, small excess amounts of adipose tissue may provide needed energy reserves during acute catabolic illnesses, have beneficial mechanical effects with some types of traumatic injuries, and convey other salutary effects that need to be investigated in light of the studies … "
Indeed, it is quite possible to be overweight and healthy, just as it’s possible to be normal weight and unhealthy. But for the vast majority of those who carry around extra pounds, health problems will often result.
The study has been heavily criticized for painting an overly simplistic picture of a very complex situation. For instance, it doesn’t tell you whether those living longer were afflicted with more chronic disease or whether their quality of life was otherwise impacted. And even more importantly, it used only BMI as a measure of body composition, and this is a highly flawed technique.
Many studies, such as one published in the Journal of the American College of Cardiology,3 have actually found that a high BMI was associated with a lower risk of death, a phenomenon known as the "obesity paradox." But these findings are typically only examples of how BMI is such a flawed measurement tool …
Why BMI is a Flawed Measurement Tool
If you'd like to know how much body fat you have and whether or not your levels put you into a weight category that might lead to health problems, most public health agencies, and therefore most physicians, promote the use of the BMI, which gauges weight in relation to height. But this method is quite flawed, as research suggests it may underestimate obesity rates and misclassify up to one-quarter of men and nearly half of women.4 According to lead author Dr. Eric Braverman, president of the nonprofit Path Foundation in New York City:5
"Based on BMI, about one-third of Americans are considered obese, but when other methods of measuring obesity are used, that number may be closer to 60%."
One of the primary reasons why BMI is such a flawed measurement tool is that it uses weight as a measure of risk, when it is actually a high percentage of body fat that makes a person have an increased disease risk. Your weight takes into account your bone structure, for instance, so a big-boned person may weigh more, but that certainly doesn't mean they have more body fat.
Athletes and completely out-of-shape people can also have similar BMI scores, or a very muscular person could be classified as "obese" using BMI, when in reality it is mostly lean muscle accounting for their higher-than-average weight. BMI also tells you nothing about where fat is located in your body, and it appears that the location of the fat, particularly if it's around your stomach, is more important than the absolute amount of fat when it comes to measuring certain health risks, especially heart disease.
Do You Know Your Body Fat Percentage?
This is another useful tool that is leaps and bounds ahead of BMI as far as gauging your weight-related health risks is concerned. It is FAR better to monitor your body fat percentage than it is your total weight, as the body fat percentage is what dictates metabolic health or dysfunction – not your total weight.
Too much body fat is linked to chronic health problems like high blood pressure, high cholesterol, heart disease, diabetes, and cancer, while too little body fat is also problematic and can cause your body to enter a catabolic state, where muscle protein is used as fuel.
Body fat calipers are one of the most trusted and most accurate ways to measure body fat. A body fat or skinfold caliper is a lightweight, hand-held device that quickly and easily measures the thickness of a fold of your skin with its underlying layer of fat. Taken at three very specific locations on your body, these readings can help you estimate the total percent of body fat within your entire body.
You can also use a digital scale that determines body fat, which is what I use personally. I use an Eat Smart Precision GetFit Body Fat Scale that I picked up from Amazon for around $50. Although many body fat measurements can be inaccurate, they are nearly all more accurate than BMI, and are particularly useful to determine whether you are gaining or losing fat. Although the absolute value may be off, the direction you are going (whether your body fat is going up or down) will be very accurate, and this is an incredibly useful measure of whether you're nearing your health goals or not. A general guideline from the American Council on Exercise is as follows:6
| Classification || Women (percent fat) || Men (percent fat) |
| Essential Fat || 10-13 percent || 2-5 percent |
| Athletes || 14-20 percent || 6-13 percent |
| Fitness || 21-24 percent || 14-17 percent |
| Acceptable || 25-31 percent || 18-24 percent |
| Obese || 32 percent and higher || 25 percent and higher |
Overweight Often Leads to Obesity…
It is quite clear that the more overweight you are, the greater the health risks become. So even if it were true that a few extra pounds are actually good for you, if you’re on a path of weight gain you’re on a slippery slope that could easily lead to obesity.
The most recent health report card issued for the United States predicts that half of all American adults will be obese by 2030. Obesity-related illness is predicted to raise national health care costs by $48 billion annually over the next two decades by adding another 7.9 million new cases of diabetes, 5 million cases of chronic heart disease and stroke, and 400,000 cancer cases…7 If you want to avoid becoming one of these statistics, I suggest you start to look at your weight as less a product of “calories in vs. calories out” and more the result of a faulty “fat switch.” According to Dr. Richard Johnson of the University of Colorado, author of The Fat Switch:
"Those of us who are obese eat more because of a faulty 'switch' and exercise less because of a low energy state. If you can learn how to control the specific 'switch' located in the powerhouse of each of your cells – the mitochondria – you hold the key to fighting obesity."
Here are some highlights that Dr. Johnson explains in detail in his book:
I highly recommend picking up a copy of this book, which has been described as the "Holy Grail" for those struggling with their weight. Dietary sugar, especially fructose, is a significant "tripper of your fat switch," which is why, if you are serious about losing weight, you'll need a comprehensive plan that includes:
- Large portions of food and too little exercise are the result of your fat switch being turned on
- Metabolic Syndrome is the normal condition that animals undertake to store fat
- Fructose-containing sugars cause obesity not by calories but by turning on the fat switch
- Effective treatment of obesity requires turning off your fat switch and improving the function of your cells' mitochondria
by Lisa Garber
August 31st, 2012
Updated 04/25/2013 at 2:28 am
Antioxidants are something of a buzz word in the natural health community, and for good reason. They scavenge cancer-causing free radicals throughout our body, which leads to improved health and healthier aging. We now have genetic evidence that antioxidants kill cancer
, and they even help improve memory. Here are the top antioxidant rich foods you probably (and should) have in your kitchen.
Top 5 Antioxidant Rich Foods
Imagine if we could simply sprinkle antioxidants onto any bland food. Good news: we can! By weight, spices have the most antioxidants of any food, with cloves bearing an Oxygen Radical Absorbance Capacity (ORAC) of about 300,000 units per 100 grams. (But please don’t consume 100 grams of cloves in one sitting!) Other powerful spices include turmeric, oregano, rosemary, cinnamon, and vanilla.
Despite being typically thought of as a junk food, chocolate is packed full of antioxidants. The key to finding more antioxidants (and less fat and sugar) in your chocolate is getting the right kind. Unsweetened cocoa powder has ORAC values of 50,000, so you can make your own healthy chocolate by combining it with real butter or coconut oil and moderate amounts of healthy sugars, like maple syrup or honey. When you’re on the move, though, reach for dark chocolate, which clocks in at about 20,000 units of antioxidants.
Depending on the brew time and bean variety, coffee has an ORAC value of up to 17,000 units. In moderate amounts, coffee health benefits
include protection against atherosclerosis, type II diabetes, depression, and even dementia.
Berries have been marketed for many years as great antioxidant rich foods. Himalayan goji berries and Acai berries have the most antioxidants—25,000 and 18,5000 respectively. For those of us saving money or buying local, however, blueberries, blackberries, and raspberries still pack quite an antioxidant punch. Dried varieties, like raisins (over 10,000 units) are good choices, too. Just be sure to avoid types loaded with added sugar.
Nuts provide numerous health benefits overall, with the health benefits of pistachios
showcasing just a handful of them. Not only are nuts a great snack rich with protein, fiber, and healthy fats, but they also provide lots of antioxidants. Pecans have an ORAC value of nearly 18,000, while walnuts, hazelnuts, pistachios, and almonds are also good choices.
There are other antioxidant rich foods, but the top 5 above should be more than enough to significantly boost your antioxidant intake. Remember to buy organic as often as possible. Organic produce contains more nutrients and antioxidants than conventionally grown varieties!
2013 Apr 24;309(16):1696-703. doi: 10.1001/jama.2013.2270.
SourceDepartment of Neurology, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark. firstname.lastname@example.org
IMPORTANCE: Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism.
OBJECTIVE: To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring.
DESIGN, SETTING, AND PARTICIPANTS: Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first. MAIN OUTCOMES AND MEASURES: Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy.
RESULTS: Of 655,615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7-4.9]) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7-10.0]). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 [95% CI, 0.9-3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 [95% CI, 1.4-6.0]) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate.
CONCLUSIONS AND RELEVANCE: Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.
- [PubMed - in process]
More Recent Articles
- Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study.
- Autism Linked to Parents, Grandparents
- Impact of age on male fertility
- J Autism Dev Disord. 2013 Mar 12. [Epub ahead of print] Parental Age and Risk of Autism Spectrum Disorders in a Finnish National Birth Cohort. Lampi KM, Hinkka-Yli-Salomäki S, Lehti V, Helenius H, Gissler M, Brown AS, Sourander A. Source Department of Child Psychiatry, University of Turku, Turku, Finland. Abstract Aim of the study was to examine the associations between parental age and autism spectrum disorders (ASD). Data were based on the FIPS-A (Finnish Prenatal Study of Autism and Autism Spectrum Disorders), a case-control study with a total of 4,713 cases with childhood autism (n = 1,132), Asperger's syndrome (n = 1,785) or other pervasive developmental disorder (PDD) (n = 1,796), which were ascertained from the Finnish Hospital Discharge Register. Controls were selected from the Finnish Medical Birth Register. Conditional logistic regression models were used for statistical analyses. Advanced paternal age (35-49 years) was associated with childhood autism in offspring, whereas advanced maternal age was associated with both Asperger's syndrome and PDD in offspring (35 years or more and 40 years or more, respectively). Teenage motherhood (19 years or less) was associated with PDD in offspring. The main finding was that maternal and paternal ages were differentially associated with ASD subtypes. In addition to advanced parental age, teenage pregnancy seems to incur a risk for PDD in offspring. PMID: 23479075 [PubMed - as supplied by publisher]
- New Studies: Flu Shots May Cause Autism