A better method of measuring neurogenesis

One of the references cited in Linking adult neurogenesis to Alzheimer’s disease was https://www.nature.com/articles/s41591-019-0375-9 “Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease” (not freely available).

This 2019 Spanish human study used improved techniques to find:

“Adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry. Direct evidence of AHN in humans has remained elusive. Determining whether new neurons are continuously incorporated into the human dentate gyrus (DG) during physiological and pathological aging is a crucial question with outstanding therapeutic potential.

By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing methods, we identified thousands of immature neurons in the DG of neurologically healthy human subjects up to the ninth decade of life. These neurons exhibited variable degrees of maturation along differentiation stages of AHN. In sharp contrast, the number and maturation of these neurons progressively declined as AD advanced.

These results demonstrate the persistence of AHN during both physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits in AD that might be amenable to novel therapeutic strategies.”


The control group was 13 neurologically healthy deceased people aged 43 to 87. The AD group was 45 deceased people, distributed among the six Braak stages of the pathology, aged 52 to 97.

Linking adult neurogenesis to Alzheimer’s disease

This 2019 Spanish human study compared DNA methylation, chromatin and histone modifications in the hippocampus of deceased Alzheimer’s disease patients with controls:

“A significant percentage of the differentially methylated genes were related to neural development and neurogenesis. It was astounding that other biological, cellular, and molecular processes generally associated with neurodegeneration such as apoptosis, autophagy, inflammation, oxidative stress, and mitochondrial or lysosomal dysfunction were not overrepresented.

The results of the present study point to neurogenesis-related genes as targets of epigenetic changes in the hippocampus affected by AD. These methylation changes might be built throughout life due to external and internal cues and would represent an example of epigenetic interaction between environmental and genetic factors in developing AD.

As an alternative explanation, these epigenetic marks might also represent the trace of DNA methylation alterations induced during early developmental stages of the hippocampus, which would remain as a fingerprint in the larger proportion of hippocampal neurons that are not exchanged. This second hypothesis would link AD to early life stages, in concordance with recent studies that revealed abnormal p-tau deposits (pre-tangles) in brains of young individuals under 30, suggesting AD pathology would start earlier in life than it was previously thought. The influence of the genetic risk for AD has also been postulated to begin in early life, and other AD risk factors may be influenced by in utero environment.”


The study cited references to adult neurogenesis:

“Though strongly related to brain development, neurogenesis is also maintained in the adult human brain, mainly in two distinct areas, i.e., the subventricular zone and the subgranular zone of the dentate gyrus in the hippocampus. There is substantial neurogenesis throughout life in the human hippocampus as it is estimated that up to one third of human hippocampal neurons are subject to constant turnover.

Adult neurogenesis is linked to hippocampal-dependent learning and memory tasks and is reduced during aging. Recent evidence suggests that adult neurogenesis is altered in the neurodegenerative process of AD, but it is still controversial with some authors reporting increased neurogenesis, whereas others show reduced neurogenesis. In the human hippocampus, a sharp drop in adult neurogenesis has been observed in subjects with AD.”

One of the study’s limitations was its control group:

“There was a significant difference in age between controls [12, ages 50.7 ± 21.5] and AD patients [26, ages 81.2 ± 12.1], being the latter group older than the former group. Although we adjusted for age in the statistical differential methylation analysis, the accuracy of this correction may be limited as there is little overlap in the age ranges of both groups.”

https://clinicalepigeneticsjournal.biomedcentral.com/track/pdf/10.1186/s13148-019-0672-7 “DNA methylation signature of human hippocampus in Alzheimer’s disease is linked to neurogenesis”

OCD and neural plasticity

This 2019 New York rodent study investigated multiple avenues to uncover mechanisms of obsessive-compulsive disorder:

“Psychophysical models of OCD propose that anxiety (amygdala) and habits (dorsolateral striatum) may be causally linked. Numerous genetic and environmental factors may reduce striatum sensitivity and lead to maladaptive overcompensation, potentially accounting for a significant proportion of cases of pathological OCD-like behaviors.

Our results indicate that both the development and reversal of OCD-like behaviors involve neuroplasticity resulting in circuitry changes in BLA-DLS and possibly elsewhere.”


The researchers explored two genetic models of OCD, showed why these insufficiently explained observed phenomena, then followed up with epigenetic investigations. They demonstrated how and the degree to which histone modifications and DNA methylation regulated both the development and reversal of OCD symptoms.

However, the researchers also carelessly cited thirteen papers outside the specific areas of the study to support one statement in the lead paragraph:

“Novel studies propose that modulations in gene expression influenced by environmental factors, are connected to mental health disorders.”

Only one of the thirteen citations was more recent than 2011, and none of them were high-quality studies.

https://www.nature.com/articles/s41598-019-45325-6.pdf “Amelioration of obsessive-compulsive disorder in three mouse models treated with one epigenetic drug: unraveling the underlying mechanism”

Transgenerational diseases caused by great-grandmother DDT exposure

This 2019 rodent study from the labs of Dr. Michael Skinner at Washington State University found:

“The exposure of a gestating female during fetal gonadal sex determination to DDT can promote the epigenetic transgenerational inheritance of obesity and disease.

Transgenerational pathologies (F3 generation) of late puberty, obesity, testis, prostate, and multiple disease were observed in the DDT lineage males. Obesity, ovarian, kidney, and multiple disease transgenerational pathologies (F3 generation) were observed in the DDT lineage females.

Epigenetic biomarkers or diagnostics provide preliminary evidence for preconception diagnosis of increased susceptibility to transgenerational disease in offspring.”


For those of us who thought DDT was discontinued:

“DDT was banned in the USA in 1973, but it is still recommended by the World Health Organization for indoor residual spray. India is by far the largest consumer of DDT worldwide.

India has experienced a 5-fold increase of type II diabetes over the last three decades with a predisposition to obesity already present at birth in much of the population. Although a large number of factors may contribute to this increased incidence of obesity, the potential contribution of ancestral toxicant exposures in the induction of obesity susceptibility requires further investigation.”

Where are the human studies of this subject? Why aren’t follow-on generations’ diseases traced to the likely sources?

How many F3 great-grandchildren of women exposed to DDT during pregnancy are alive today? Millions, tens of millions?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536675 “Sperm epimutation biomarkers of obesity and pathologies following DDT induced epigenetic transgenerational inheritance of disease”

Infant DNA methylation and caregiving

This 2019 US human study attempted to replicate findings of animal studies that associated caregiver behavior with infant DNA methylation of the glucocorticoid receptor gene:

“Greater levels of maternal responsiveness and appropriate touch were related to less DNA methylation of specific regions in NR3c1 exon 1F, but only for females. There was no association with maternal responsiveness and appropriate touch or DNA methylation of NR3c1 exon 1F on prestress cortisol or cortisol reactivity. Our results are discussed in relation to programming models that implicate maternal care as an important factor in programing infant stress reactivity.”


The study had many undisclosed and a few disclosed limitations, one of which was:

“Our free-play session, while consistent with the length of free-play sessions in other studies, was short (5 min). It is unclear whether a longer length of time would have yielded significant different maternal responsiveness and appropriate touch data.”

The final sentence showed the study’s purpose was other than discovering factual evidence:

“Following replication of this work, it could ultimately be used in conjunction with early intervention, or home-visiting programs, to measure the strength of the intervention effect at the epigenetic level.”

https://onlinelibrary.wiley.com/doi/full/10.1002/imhj.21789 “DNA methylation of NR3c1 in infancy: Associations between maternal caregiving and infant sex” (not freely available)

What drives cellular aging?

This 2019 US/UK human cell study by the founder of the epigenetic clock method investigated epigenetic aging:

“It is widely assumed that extension of lifespan is a result of retardation of ageing. While there is no counter-evidence to challenge this highly intuitive association, supporting empirical evidence to confirm it is not easy to acquire.

The scarcity of empirical evidence is due in part to the lack of a good measure of age that is not based on time. In this regard, the relatively recent development of epigenetic clocks is of great interest.

At the cellular level more is known, but from the perspective of what epigenetic ageing is not, rather than what it is. While we still do not know what cellular feature is associated with epigenetic ageing, we can now remove:

  • somatic cell differentiation

from the list of possibilities and place it with

  • cellular senescence,
  • proliferation and
  • telomere length maintenance,

which represent cellular features that are all not linked to epigenetic ageing.”


The study used several agents, including rapamycin, to investigate the hypotheses. Rapamycin isn’t a panacea, but:

“The ability of rapamycin to suppress the progression of epigenetic ageing is very encouraging for many reasons not least because it provides a valuable point-of-entry into molecular pathways that are potentially associated with it. Evidently, the target of rapamycin, the mTOR complex is of particular interest.

The convergence of the GWAS observation with the experimental system described here is a testament of the strength of the skin & blood clock in uncovering biological features that are consistent between the human level and cellular level. It lends weight to the emerging view that the mTOR pathway may be the underlying mechanism that supports epigenetic ageing.”

The limitation section ended with:

“It is important to note that it is inadvisable (actively discouraged) to directly extrapolate the studies here, especially in terms of the magnitude of age suppression, to potential effects of rapamycin on humans.”

https://www.aging-us.com/article/101976/text “Rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation”