- Blood levels of D-serine are reduced in older individuals compared to young ones.
- D-serine synthesis is modulated by a protein called Menin, which mitigates bone, skin, and brain aging while increasing mouse lifespan by about 10%.
- Supplementing aged mice with D-serine improves their memory but does not recapitulate the body-wide anti-aging effects of Menin.
If there were a region of the brain that could regulate the aging of the entire body, it would be the hypothalamus. Age-associated damage to the hypothalamus, such as damage caused by inflammation, could explain detrimental features of aging, such as reproductive decline, shifts in circadian rhythms, and growth hormone imbalances. Now, a study from Xiamen University in China suggests the hypothalamus could modulate the aging of multiple organs.
The study, published in PLOS Biology, provides evidence to support that altered D-serine synthesis in the hypothalamus contributes to aging. Leng and colleagues find that older individuals have low levels of D-serine in their blood. They then show that Menin, a protein that modulates D-serine synthesis, slows multiple-organ aging and increases the lifespan of mice. Finally, they show that supplementing aged mice with D-serine mitigates memory loss.
Dysregulated D-Serine Synthesis Leads to Aging
In a previous study, Leng and colleagues found that Menin may inhibit the activation of inflammation in the hypothalamus. The authors say:
“We speculate that the decline of Menin expression in the hypothalamus with age may be one of the driving factors of aging…”
To study this, the China-based researchers established a mouse model lacking Menin in the hypothalamus. Not only did the Menin-lacking mice display increased hypothalamic inflammation, they also exhibited aging symptoms such as reduced muscle size, bone mass, and skin thickness. Moreover, Menin-lacking mice showed signs of impaired learning and memory and had shortened lifespans.
Analysis of gene activation patterns showed that D-serine synthesis was altered in the Menin-lacking mice. Therefore, the researchers measured D-serine from the blood serum of older adults (aged 83 to 94) and younger adults (aged 22 to 26). They found that D-serine levels were lower in the older adults, suggesting that age-associated inflammation of the hypothalamus could be due to altered Menin signaling, leading to D-serine deficiency.
“It is plausible that decreased Menin signaling contribute to the activated neuroinflammation in the hypothalamus,” state the authors.
Upon experimentation, Leng and colleagues found that Menin increases the activity of the enzyme responsible for synthesizing D-serine. To explore this, they injected the hypothalamus of aged mice (20 months of age) with Menin via an adeno-associated virus (AAV) delivery system, which can be considered a type of gene therapy. AAV delivery of Menin was shown to increase D-serine levels and the enzyme responsible for its synthesis.
Furthermore, AAV-mediated Menin elevation reversed aging symptoms such as thin skin, reduced bone mass, and cognitive deficits. Importantly, increasing Menin in the hypothalamus of aged mice prolonged their median lifespan by approximately 10%. These findings suggest that disruptions in hypothalamic Menin and D-serine synthesis contribute to skin, bone, and brain aging.
To test this, the researchers gave 22-month-old mice and Menin-lacking mice D-serine in their drinking water for 3 weeks (approximately 100 mg/kg/day). This led to an increase in D-serine in the serum, hypothalamus, and hippocampus of the mice. D-serine supplementation was also shown to rescue cognitive deficits, especially in the Menin-lacking mice. Learning and memory was shown to be improved in the aged mice by the Y-maze test and T-maze test.
It should be pointed out that, unlike Menin gene therapy, D-serine supplementation did not reverse non-brain aspects of aging like bone loss and skin thinning. The authors attribute this to too short a duration of D-serine supplementation (30 days) or Menin’s effects on organs outside the skull:
“Our data indicates that the remission of aging phenotype by D-serine is limited to cognitive improvement, leaving peripheral systems aging phenotypes unchanged. This may be due to the limited time of D-serine supplement, or there are other downstream pathways regulated by Menin that contributes to peripheral aging regulation.”
Taking D-Serine to Boost Memory in Old Age
The findings of Leng and colleagues suggest that D-serine supplementation could treat cognitive decline. Furthermore, Menin gene therapy could counter the aging of multiple tissues by targeting the declining hypothalamus.
“These results indicate Menin as a novel arbiter for systemic aging and the therapeutic potential for D-serine in treatment against cognitive decline,” the authors say.
Notably, the development of potential therapies targeting Menin will require much more investigation. In contrast, D-serine, along with its precursor L-serine, can be found in supplement form. However, clinical studies are needed to support its memory-boosting and anti-brain aging effects in humans.