Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human-specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience.

Healthy elderly people have the potential to remain cognitively and emotionally more intact than commonly believed, due to the persistence of AHN into the eighth decade of life. However, reduced cognitive-emotional resilience may be caused by a variety of factors such as a smaller quiescent neural progenitor pool, diminished angiogenesis, or decreasing neuroplasticity in the anterior DG.

Given the different functions of the rostral and caudal DG (), we assessed the anterior, mid, and posterior hippocampus postmortem from 28 women and men 14 to 79 years of age. In each region, we characterized and quantified angiogenesis, volume, and cells at different maturational stages in the DG neurogenic niche, using unbiased stereological methods (). To avoid confounders, subjects studied had no neuropsychiatric disease or treatment.

Functional dissociation of adult-born neurons along the dorsoventral axis of the dentate gyrus.

AHN and angiogenesis are co-regulated (). Exercise enhances cerebral blood volume, which results in more AHN in mice and better cognitive performance in humans (), but it may have a reduced impact in older people (). Thus, we quantified AHN, angiogenesis, and DG volume and their relationship in people of different ages, hypothesizing that they would concurrently decrease with aging and correlate with each other.

An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus.

VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants.

Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke.

Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression.

Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression.

In vivo brain imaging studies reported conflicting findings regarding age-related changes in specific hippocampal regions. While some studies observed age-related declines in anterior hippocampal volume (), others found no volume change (), or altered hippocampal shape rather than volume (). Efforts to evaluate AHN in vivo face limitations due to inadequate spatial resolution and the inability to accurately differentiate hippocampal sub-regions ().

Phylogenetic differences between humans and rodents mandate assessment of the different stages of neuronal maturation in the human DG. For example, striatal neurogenesis is found only in humans (), while olfactory bulb neurogenesis is absent in humans () but present in other mammals. Previous analyses of human AHN did not address the effects of aging, although studies have examined AHN in older populations (). The density of doublecortin-positive (DCX+) cells were reported to decline from birth into the tenth decade of life () in parallel withC-determined neuron turnover (); however, medication and drug use, which affect AHN (), were not addressed (). Using histological techniques that could not distinguish mature and immature neurons, several groups estimated that DG neurons did not decline in aging humans ().

Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease.

Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease.

Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years.

Benzodiazepines and the potential trophic effect of antidepressants on dentate gyrus cells in mood disorders.

Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years.

Healthy aging is crucial in a growing older population (). The ability to separate similar memory patterns () and recover from stress () may depend on adult hippocampal neurogenesis (AHN), which is reported to decline with aging in nonhuman primates () and mice (). New neurons are generated in the dentate gyrus (DG) of the adult human hippocampus, even after middle age (), but the extent to which neurogenesis occurs in humans is highly debated and quantitative studies are scarce.

Reversible effect of X-irradiation on proliferation, neurogenesis, and cell death in the dentate gyrus of adult mice.

There was an age-associated decline in angiogenesis in males and females, correlating with less neuroplasticity as represented by PSA-NCAM+ neuronal cells of different morphologies. Mature GN, glia, and DG volume were similar in people 14 to 79 years of age of both genders.

There was no age-related change in the number of NeuN+ GNs or Nissl+ glia estimated using stereology, nor in the volume of the DG or the GCL-SGZ in anterior, mid, and posterior hippocampus of both genders ( Figures 3 E–3F, 3H, and 3I and Figures 4 H and 4I; Video S4 ), as estimated using the Cavalieri method ().

We found smaller total capillary area and length and shorter and less branched capillaries correlating with fewer PSA-NCAM+ cells selectively in anterior-mid DG ( Figures 4 D–4G and S2–S4 ). There was no correlation between a decline in capillary measures and the number of Sox2+, nestin+, Sox2/nestin+, Ki-67+, DCX+, DCX/PSA-NCAM+, NeuN+ cells, Nissl+ glia, or DG volume, regardless of gender (data not shown).

We estimated the volume of the anterior, mid, and posterior DG, including the volumes of GCL, molecular layer (ML), and SGZ, using the Cavalieri method (), as previously reported (). We aligned outlines of the DG including SGZ, GCL, and ML ( Figure 3 E) from the most rostral to the most caudal hippocampal sections ( Video S4 ), and we used them to calculate the volume of the anterior, mid, and posterior DG and SGZ-GCL.

Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease.

Nestin is a marker of newly formed blood vessels () and co-labels with collagen-IV, a vascular basement membrane marker, and platelet/endothelial cell adhesion molecule (PECAM, or CD31), a marker of endothelial cells (). Nestin+ newly formed capillaries display distinct tube-like structure, clearly distinguishable from nestin+ INPs with a clear soma and processes ( Figures 1 G–1H and Figures 4 A–4C). We assessed angiogenesis in anterior, mid, and posterior DG by measuring the length, area, and number of bifurcations of nestin+ remodeling capillaries and the number of new capillaries per mmthroughout the tissue section thickness (50 μm) using Stereo Investigator and Neurolucida software (MBF), as previously described ().

(B) Differential interference contrast image of the quadrant in (A); nestin+ progenitors (green arrows) and capillaries (red arrows) are shown.

(A) Nestin+ capillaries and neural progenitors and Nissl+ granule cells and glia; the outlined DG region was used to quantify cell numbers and DG volume.

Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression.

Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression.

Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression.

Here we report results related to angiogenesis measures, including the number of new capillaries per cubic mm, new capillary area and length, and the number of bifurcations per capillary, as well as the estimated total number of mature GNs and glia and DG volume, in the anterior, mid, and posterior hippocampal region from individuals 14 to 79 years of age.

Decreased Angiogenesis and Capillary Density in Aged Brains Correlates with Reduced Neuroplasticity while GN, Glia, and DG Volume Remain Unchanged

We did not see an age-related decline of DCX+ and DCX/PSA-NCAM+ INPs and immature neurons, suggesting stable neurogenesis in older humans of both sexes. The finding of fewer PSA-NCAM+ cells of different morphologies ranging from type II INPs to mature neuron morphologies most likely represents a decline in neuroplasticity in aging humans, which could include blunted migration, dendrite sprouting, long-term potentiation, and activity-dependent plasticity.

Conversely, we found stable numbers of DCX+ and DCX/PSA-NCAM+ cells across the 65-year age span in both genders ( Figures 3 A–3C, 3G , and S1 D–S1F), representing preserved type III INP and immature GN numbers (), which were in the order of a few thousands per DG region (anterior, mid, or posterior). Although we detected some DCX+ processes, they were rarely seen in adult human INPs ( Figures 3 A–3C and S1 D; Video S2 ), as expected based on previous reports (). We confirmed PSA-NCAM/NeuN co-labeling, with most NeuN+ GNs not expressing PSA-NCAM ( Figure 3 D; Video S3 ).

(E) NeuN+ neurons in the granule cell layer (GCL), the molecular layer (ML), and subgranular zone (SGZ) are outlined; these outlines were used to calculate DG and GCL-SGZ volumes.

(B and C) DCX+ cells in SGZ, without and with stained processes.

(A) Polysialylated neural cell adhesion molecule (PSA-NCAM) and doublecortin (DCX) expression in an immature neuron between subgranular zone (SGZ) and granule cell layer (GCL), two PSA-NCAM+/DCX− cells, and 4’,6-diamidino-2-phenylindole (DAPI)+ nuclei.

Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years.

We found that PSA-NCAM+ cells in human SGZ, showing morphologies of INPs and immature GNs, and PSA-NCAM+ mature GNs were all fewer in anterior DG with older age, in both males and females, and had stable and cell-type-specific perikaryon volumes ( Figures 2 A–2G).

(A) PSA-NCAM+ cells in subgranular zone (SGZ) and granule cell layer (GCL) with processes projecting into the molecular layer (ML).

PSA-NCAM was detected in neural cells with immature, bipolar, and pyramidal morphology and is considered a marker of neuroblasts or immature GNs only when co-labeled with DCX (); however, when found alone and on cells of different morphologies, it is considered a marker of neuroplasticity ().

To test age-related changes in type II-III INPs and immature GNs, as well as activity-dependent neuroplasticity or migration, we used markers specific for this maturational phase.

In summary, the Sox2+ QNP pool was smaller in the anterior-mid DG of older people and comprised approximately 1,000 cells per DG region (anterior, mid, or posterior), while nestin+ and Sox2/nestin+ INP type I-II cells, in the range of thousands per DG region, were not fewer in older humans in anterior, mid, or posterior DG. Ki-67+ cells, unchanged between 14 and 79 years of age, were in the order of 10,000 per DG region, likely including dividing cells of non-neuronal lineage (likely endothelial and glial cells).

We assessed the first steps of neurogenesis, specifically the abundance of QNP and type I-II INP cells in the anterior, mid, and posterior DG of 28 males (n = 17) and females (n = 11) between 14 and 79 years of age. Expression of transcription factor Sox2, required for maintenance of multipotent neural stem cells (), labeled QNPs and declined with aging selectively in anterior-mid DG, regardless of gender; GFAP also labeled QNPs, showing the typical radial-glia-like morphology, with apical processes ( Figures 1 A–1E, 1M , and S1 A; Video S1 ). Sox2/nestin+ and nestin+ type I-II INPs () showed distinct perikaryon and multipolar processes, contacting nestin+ remodeling capillaries () in the neurogenic niche of the subgranular zone (SGZ, Figures 1 E–1H and Figures 4 A–4C), as we reported earlier (), and did not decline with age in human anterior, mid, or posterior DG in males or females ( Figures 1 N, S1B, and S1C). Nestin+ proliferating type II INPs also co-labeled with Ki-67, a marker of active cell cycle (), and were found in the SGZ as seen in mice, and in the granule cell layer (GCL) ( Figures 1 F and 1I–1L), as we have shown in humans () and as others have found in nonhuman primates (). Ki-67+ cells were stable between 14 and 79 years of age in human anterior, mid, and posterior DG in both sexes ( Figure 1 O).

(N and O) Nestin+ and Ki-67+ cells do not decline with older age in anterior, mid, or posterior DG.

(C) Sox2+ type I QNPs in the subgranular zone (SGZ) with apical processes crossing the granule cell layer (GCL) into the molecular layer (ML).

Continuation of neurogenesis in the hippocampus of the adult macaque monkey.

Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression.

The Ki-67 protein: from the known and the unknown.

Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression.

The generation of new neurons in the DG neurogenic niche starts from quiescent radial-glia-like type I neural progenitor cells (QNPs) expressing glial fibrillary acid protein (GFAP), sex determining region Y-box 2 (Sox2), brain lipid-binding protein (BLBP), and nestin (). QNPs undergo asymmetric divisions and generate amplifying, or type II, intermediate neural progenitors (INPs) expressing Ki-67 and nestin (). As type II INPs differentiate into neuroblasts, or type III INPs, they lose the expression of Sox2 and GFAP while gaining expression of DCX and polysialylated neural cell adhesion molecule (PSA-NCAM), which is also expressed by immature and mature granule neurons (GNs) (). GNs are the final product of the differentiation cascade and express neuronal nuclear marker (NeuN), Prox-1, calbindin, and βIII-tubulin (). In anterior, mid, and posterior DG, we characterized and quantified the following: QNPs expressing GFAP, Sox2, and nestin; type I and II INPs expressing Ki-67 and nestin; neuroblasts, or type III INPs, and immature GNs expressing DCX and PSA-NCAM; and finally, mature GNs expressing NeuN. The anterior DG was defined as the portion from the most rostral appearance of the DG to the start of the lateral geniculate (visible in coronal brain sections); the mid DG spanned the lateral geniculate; and the posterior DG went from the end of the lateral geniculate to the caudal end of the DG.

Discussion

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