Testosterone Improves Age-Related Cognitive Decline in Rats

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Written by Brett Weiss

June 20, 2021

Supplementing with the hormone enhances the function of the cell’s power-generating structure (mitochondria) in aged rat neurons and ameliorates cognitive decline.

Image by Pete Linforth from Pixabay


  • Testosterone supplementation ameliorates age-related cognitive decline in male rats.
  • Supplementing with the hormone preserves neurons and improves the function of their mitochondria.
  • These findings could aid the design of testosterone-based therapeutics for age-related cognitive decline.

Dysfunctional energy-generating structures in cells – mitochondria – are a common characteristic of normal aging and likely play a key role in neurodegenerative diseases like Alzheimer’s and Parkinson’s diseases. What’s more, age-related reduced testosterone levels correlate with the onset of these diseases, and supplementing with testosterone improves cognitive and motor symptoms. But a clear connection between supplementing testosterone and improved mitochondrial function hadn’t been established, until now.

Shi and colleagues from Hebei Medical University in China published a study in Aging showing that testosterone replacement therapy ameliorates age-associated brain mitochondrial dysfunction and promotes enhanced cognition in aged rats. Importantly, they show that injecting rats with 1 mg/kg per day of testosterone improved rat cognitive function, attenuated neuronal loss and dysfunction, and restored neuronal mitochondria function. “These findings suggest that testosterone supplementation may be a viable approach to ameliorating brain mitochondrial dysfunction and thus prevent or treat cognitive-behavioral deficits and neurodegenerative conditions associated with aging,” said Shi and colleagues.

Testosterone Supplementation Attenuates Age-Related Cognitive Decline

To figure out whether testosterone supplementation attenuated cognitive decline, Shi and colleagues performed field tests where they placed rats in the center of a box. Twenty-four-month-old rats performed substantially worse at exploring their surroundings compared to their younger, six-month-old counterparts. Supplementing the aged rats with testosterone restored their climbing, rearing, and sniffing exploratory behavior, indicative of improved cognition.

(Yan et al., 2021 | Aging) Testosterone supplementation ameliorates age-related cognitive decline in male rats. While testosterone therapy did not affect the amount of walking (A) in field tests, it substantially improved climbing (B), rearing (C), and sniffing (D) behaviors in aged male rats. These findings indicate that overall, testosterone therapy significantly improved exploratory behavior, an indicator of cognitive function, in aged male rats.

Testosterone Replacement Prevents Age-Related Neuron Loss and Dysfunction

Shi and colleagues then sought to figure out whether they could trace testosterone-induced cognitive enhancements in aged rats to improved neuronal structural and functional integrity. In order to do so, they looked at the condensation of chromosomes in cells’ nuclei (karyopyknosis) that shows neurons are either dead or dying. Although much higher levels of karyopyknosis were seen in aged rat neurons, testosterone therapy reversed the buildup of these karyopyknotic neurons. These findings showed that testosterone therapy mitigates age-related neuronal loss and dysfunction.

(Yan et al., 2021 | Aging) Testosterone supplementation substantially improves neuronal integrity during aging. A region of the brain involved in learning and memory formation – the hippocampus – is shown for young rats (A), old rats (B), and old rats treated with testosterone (C). The top row shows a section of the hippocampus and the bottom row shows 10 X magnifications. The dark blue stains that are more abundant in the aged, 24-month-old mice (B) indicate chromosome condensation (karyopyknosis). Testosterone therapy ameliorates karyopyknosis in aged male rat neurons as quantified the graph (D).

Supplementing with Testosterone Improves Mitochondrial Function in Aged Rats

Since mitochondrial dysfunction is intimately tied to age-related neuronal malfunction and since testosterone therapy improves cognition and neuronal integrity, Shi and colleagues set out to show the link between testosterone-enhanced cognition and improved mitochondrial function. The research team looked at mitochondrial membrane potential – the ability of the mitochondrial membrane to separate oppositely charged ions – an indicator of membrane integrity. Shi and colleagues found a reduced mitochondrial membrane potential in aged rats but that testosterone supplementation restored the membrane potential. These findings indicate that testosterone therapy improves brain mitochondrial function in aged rats and provides the sought-after link between testosterone therapy-induced cognitive enhancement and improved mitochondrial health.

(Yan et al., 2021 | Aging) Testosterone supplementation improves mitochondrial function in aged male rat neurons. The dye rhodamine123 was used to measure the membrane potential of mitochondrial membranes in the brain regions called the substantia nigra (A) and the hippocampus (B). In both brain regions, ion permeability diminished with age, but testosterone therapy substantially increased mitochondrial membrane potential in aged male rat neurons.

The Findings May Help in Testosterone-Based Therapy Design

“Our study revealed that testosterone supplementation improved exploratory behavior, attenuated neuronal dysfunction and neuronal loss, and ameliorated mitochondrial dysfunction,” stated Shi and colleagues. Findings from the study provide a clear link between testosterone-induced enhanced cognition and improved mitochondrial function in aged male rats. Figuring out details on how testosterone facilitates enhanced mitochondrial function and improves cognition will require further research.

“Our findings may be relevant for the design of testosterone-based therapies aimed at preventing or treating cognitive-behavioral deficits and diseases associated with aging,” said Shi and colleagues. Since these findings came from research on male rats, future studies will need to look at how well we can apply testosterone therapy to brain health for aging human males. Moreover, the study didn’t examine hormone replacement therapy in aging females with cognitive decline, so figuring out the intricacies of hormone levels in both sexes will require further work.

Story Source

Yan W, Zhang T, Kang Y, Zhang G, Ji X, Feng X, Shi G. Testosterone ameliorates age-related brain mitochondrial dysfunction. Aging (Albany NY). 2021 Jun 17;13. doi: 10.18632/aging.203153. Epub ahead of print. PMID: 34139672.

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