Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study.

BACKGROUND: Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown. OBJECTIVE: To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes. DESIGN: Nationwide prospective registry-based cohort study. SETTING: Denmark from 1997 to 2016. PARTICIPANTS: All liveborn singletons from mothers without histories of diabetes or essential hypertension. MEASUREMENTS: Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings. RESULTS: Of 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073). LIMITATION: Information on underlying disease status was limited. CONCLUSION: Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation. PRIMARY FUNDING SOURCE: National Institutes of Health.

Balsalazide Exposure During the Development of Fertilizing Sperm May Be Associated With Offspring Birth Defects.

We report an association between balsalazide exposure during the development of fertilizing sperm and birth defects in offspring. Exposed offspring were approximately 8 times more likely to have a birth defect. There were no pre-existing reasons to suspect such a relationship, which should be confirmed in other data.

The Danaid Theory of Aging.

The classical evolutionary theories of aging suggest that aging evolves due to insufficient selective pressure against it. In these theories, declining selection pressure with age leads to aging through genes or resource allocations, implying that aging could potentially be stalled were genes, resource allocation, or selection pressure somewhat different. While these classical evolutionary theories are undeniably part of a description of the evolution of aging, they do not explain the diversity of aging patterns, and they do not constitute the only possible evolutionary explanation. Without denying selection pressure a role in the evolution of aging, we argue that the origin and diversity of aging should also be sought in the nature and evolution of organisms that are, from their very physiological make up, unmaintainable. Drawing on advances in developmental biology, genetics, biochemistry, and complex systems theory since the classical theories emerged, we propose a fresh evolutionary-mechanistic theory of aging, the Danaid theory. We argue that, in complex forms of life like humans, various restrictions on maintenance and repair may be inherent, and we show how such restrictions are laid out during development. We further argue that there is systematic variation in these constraints across taxa, and that this is a crucial factor determining variation in aging and lifespan across the tree of life. Accordingly, the core challenge for the field going forward is to map and understand the mosaic of constraints, trade-offs, chance events, and selective pressures that shape aging in diverse ways across diverse taxa.

Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception.

OBJECTIVE: With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the 3 months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone. RESULTS: For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). Our evidence suggests that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. For the other drugs investigated larger exposures are needed for conclusive statements.

The Rarity of Survival to Old Age Does Not Drive the Evolution of Senescence.

The evolution of senescence is often explained by arguing that, in nature, few individuals survive to be old and hence it is evolutionarily unimportant what happens to organisms when they are old. A corollary to this idea is that extrinsically imposed mortality, because it reduces the chance of surviving to be old, favors the evolution of senescence. We show that these ideas, although widespread, are incorrect. Selection leading to senescence does not depend directly on survival to old age, but on the shape of the stable age distribution, and we discuss the implications of this important distinction. We show that the selection gradient on mortality declines with age even in the hypothetical case of zero mortality, when survivorship does not decline. Changing the survivorship function by imposing age independent mortality has no affect on the selection gradients. A similar result exists for optimization models: age independent mortality does not change the optimal result. We propose an alternative, brief explanation for the decline of selection gradients, and hence the evolution of senescence.

Size, longevity and cancer: age structure.

There is significant recent interest in Peto's paradox and the related problem of the evolution of large, long-lived organisms in terms of cancer robustness. Peto's paradox refers to the expectation that large, long-lived organisms have a higher lifetime cancer risk, which is not the case: a paradox. This paradox, however, is circular: large, long-lived organisms are large and long-lived because they are cancer robust. Lifetime risk, meanwhile, depends on the age distributions of both cancer and competing risks: if cancer strikes before competing risks, then lifetime risk is high; if not, not. Because no set of competing risks is generally prevalent, it is instructive to temporarily dispose of competing risks and investigate the pure age dynamics of cancer under the multistage model of carcinogenesis. In addition to augmenting earlier results, I show that in terms of cancer-free lifespan large organisms reap greater benefits from an increase in cellular cancer robustness than smaller organisms. Conversely, a higher cellular cancer robustness renders cancer-free lifespan more resilient to an increase in size. This interaction may be an important driver of the evolution of large, cancer-robust organisms.

Intrinsic and extrinsic mortality reunited.

Intrinsic and extrinsic mortality are often separated in order to understand and measure aging. Intrinsic mortality is assumed to be a result of aging and to increase over age, whereas extrinsic mortality is assumed to be a result of environmental hazards and be constant over age. However, allegedly intrinsic and extrinsic mortality have an exponentially increasing age pattern in common. Theories of aging assert that a combination of intrinsic and extrinsic stressors underlies the increasing risk of death. Epidemiological and biological data support that the control of intrinsic as well as extrinsic stressors can alleviate the aging process. We argue that aging and death can be better explained by the interaction of intrinsic and extrinsic stressors than by classifying mortality itself as being either intrinsic or extrinsic. Recognition of the tight interaction between intrinsic and extrinsic stressors in the causation of aging leads to the recognition that aging is not inevitable, but malleable through the environment.

Interaction mortality: senescence may have evolved because it increases lifespan.

Given an extrinsic challenge, an organism may die or not depending on how the threat interacts with the organism's physiological state. To date, such interaction mortality has been only a minor factor in theoretical modeling of senescence. We describe a model of interaction mortality that does not involve specific functions, making only modest assumptions. Our model distinguishes explicitly between the physiological state of an organism and potential extrinsic, age-independent threats. The resulting mortality may change with age, depending on whether the organism's state changes with age. We find that depending on the physiological constraints, any outcome, be it 'no senescence' or 'high rate of senescence', can be found in any environment; that the highest optimal rate of senescence emerges for an intermediate physiological constraint, i.e. intermediate strength of trade-off; and that the optimal rate of senescence as a function of the environment is driven by the way the environment changes the effect of the organism's state on mortality. We conclude that knowledge about the environment, physiology and their interaction is necessary before reasonable predictions about the evolution of senescence can be made.

No senescence despite declining selection pressure: Hamilton's result in broader perspective.

Theory predicts that senescence should inevitably evolve because selection pressure declines with age. Yet, data show that senescence is not a universal phenomenon. How can these observations peacefully coexist? Evolution of any trait hinges on its impact on fitness. A complete mathematical description of change in fitness, the total fitness differential, involves selection pressure along with a perturbation function that describes how the vital rates, mortality and fecundity, are affected across ages. We propose that the perturbation function can be used to model trade-offs when vital rates are perturbed in different directions and magnitude at different ages. We find that for every trade-off we can identify parameter values for which senescence does evolve and others for which it does not. We argue that this reconciles the apparent contradiction between data and theory. The total fitness differential is also instrumental in deriving mathematical relationships between alternative indicators of selection pressure. We show examples and highlight that any indicator combined with the right perturbation function can be used to parameterize a specific biological change. Biological considerations should motivate what perturbation functions are used. We interpret the relevance of Hamilton's finding that selection pressure declines for the evolution of senescence: declining selection pressure is a necessary but not a sufficient condition.

The maintenance gap: a new theoretical perspective on the evolution of aging.

One of the prevailing theories of aging, the disposable soma theory, views aging as the result of the accumulation of damage through imperfect maintenance. Aging, then, is explained from an evolutionary perspective by asserting that this lack of maintenance exists because the required resources are better invested in reproduction. However, the amount of maintenance necessary to prevent aging, 'maintenance requirement' has so far been largely neglected and has certainly not been considered from an evolutionary perspective. To our knowledge we are the first to do so, and arrive at the conclusion that all maintenance requirement needs an evolutionary explanation. Increases in maintenance requirement can only be selected for if these are linked with either higher fecundity or better capabilities to cope with environmental challenges to the integrity of the organism. Several observations are suggestive of the latter kind of trade-off, the existence of which leads to the inevitable conclusion that the level of maintenance requirement is in principle unbound. Even the allocation of all available resources to maintenance could be unable to stop aging in some organisms. This has major implications for our understanding of the aging process on both the evolutionary and the mechanistic level. It means that the expected effect of measures to reallocate resources to maintenance from reproduction may be small in some species. We need to have an idea of how much maintenance is necessary in the first place. Our explorations of how natural selection is expected to act on the maintenance requirement provides the first step in understanding this.

Elevated CRP levels are associated with increased carotid atherosclerosis independent of visceral obesity.

BACKGROUND: Visceral obesity (VO) is associated with an increased risk of cardiovascular disease. Elevated C-reactive protein (CRP) levels are associated with VO and cardiovascular disease. After exploring the relation between CRP and VO, we aimed to evaluate the VO independent relation between CRP and carotid atherosclerosis. METHODS AND RESULTS: The prevalence of inflammation was evaluated in 439 male subjects with VO without type 2 diabetes and manifest cardiovascular disease. Waist circumference significantly correlated with CRP (r: 0.20, p<0.001). However, 18.2% of patients in the waist circumference group 94-102 had elevated CRP levels while 9.6% of patients in the waist circumference group >118 cm had low CRP levels. From the 439 subjects, 40 subjects were prospectively selected for MRI assessment of carotid atherosclerosis and visceral and subcutaneous adipose tissue distribution in a case-control setting matching for age and waist circumference. Twenty male subjects with age >50 years with CRP levels >2.5mg/L (CRP+) were compared to 20 controls with CRP levels <1.8 mg/L (CRP-). Maximum vessel wall thickness in CRP+ was significantly higher both in the common carotid artery (15%, p<0.01) and the bulb region (18%, p<0.01). The distribution of fat in visceral and subcutaneous deposits was not significantly different between CRP+ and CRP-. CONCLUSION: Elevated CRP levels are associated with significantly increased maximum vessel wall thickness independent of VO and of MRI measured adipose tissue distribution, both in the common carotid artery and the carotid bulb.