A recent study described a process called ferro-aging, in which iron accumulation leads to oxidative damage and cellular senescence. This process can be delayed by Vitamin C [1].
A two-faced atom
Iron, like many components of biological systems, has two faces. On the one hand, it’s essential for developmental and metabolic processes [2, 3]. On the other hand, it is a catalyst for reactive oxygen species (ROS) generation and lipid peroxidation, processes that are linked to aging [4-6].
While disruptions in iron metabolism and iron-dependent programmed cell death (ferroptosis) have been linked to multiple age-related diseases [7-11], there is still an unsolved question of whether “aging involves a coordinated, iron-dependent metabolic program that promotes cellular senescence and progressive organ decline”. This study was created to address this question.
Defining ferro-aging
The researchers began by assessing iron accumulation across multiple human cellular aging models, including human mesenchymal stem cells induced to senesce, cells expressing mutated genes associated with various accelerated aging diseases (progerias), and terminally differentiated cells. In aged or senescent cells, they detected iron accumulation as well as changes in gene expression related to iron metabolism, including one of the drivers of lipid peroxidation, the lipid-metabolism enzyme ACSL4, which plays a role in the metabolism of long-chain polyunsaturated fatty acids (PUFAs). In line with those observations, they also reported increased levels of ROS, membrane lipid peroxidation, and the lipid peroxidation end-product malondialdehyde (MDA).
These cell culture observations prompted experiments on the organismal level. A serum sample from elderly humans also showed increased free ferrous iron, a highly redox-active form of iron that contributes to ROS generation, along with the iron storage protein ferritin (FTH). Peripheral blood mononuclear cells showed higher ACSL4 and MDA levels. Iron deposition and increased markers of lipid peroxidation, including ACSL4, were also observed in samples from multiple organs of aged human tissues and cynomolgus monkeys.
The authors proposed the term ‘ferro-aging’ to describe these processes, which they believe to constitute a “coordinated program” in which iron accumulation leads to oxidative damage and thus cellular senescence.
Further experiments confirmed a causal role of iron in senescence. The researchers treated cells in cultures with two different forms of iron. Both treatments increased iron levels, ACSL4, and MDA while inducing senescence.
ACSL4 levels were consistently elevated across various iron overload-induced senescence experiments, suggesting that it may play a central role in this process. Overexpressing ACSL4 in cell cultures led to elevated lipid peroxidation and accelerated senescence, whereas knocking down its activity in senescent cells reduced lipid peroxidation and reversed senescence phenotypes.
The key roles of iron and ACSL4 were confirmed in mouse experiments. The researchers fed 5-month-old mice a high-iron diet for 2 months. As in cell cultures, multiple tissues in mice exposed to high iron levels showed increased lipid peroxidation, senescence, and inflammatory markers. At the functional level, those mice exhibited impaired cognitive function, reduced exploratory behavior, diminished muscle strength and endurance, and poorer motor coordination.
Additionally, aged mice, like primates, had increased hepatic ACSL4 levels and lipid peroxidation. To test whether decreasing those levels would have geroprotective properties, the researchers designed a genetically engineered virus to inactivate ACSL4 in the livers of aged mice. A single dose of this treatment improved cognitive function, exploratory behavior, and motor coordination, as well as markers of liver function and senescence. Similar effects were seen in a mouse model of progeria.
Fighting back
Knowing the molecular processes that contribute to aging is one thing, but finding a way to counteract them is another. These researchers moved beyond describing a process of ferro-aging to addressing how to remedy it. For this, they performed a screen of a selected library of 100 molecules previously linked to ferroptosis-related pathways. The most potent hit from the screen was vitamin C. It was able to reduce lipid peroxidation, partially restore senescent cells’ self-renewal capacity, and suppress both ferro-aging biomarkers and hallmarks of cellular senescence.
Further investigation into the mechanism of vitamin C’s effectiveness revealed that it binds to the central regulator of ferro-aging, ACSL4, and strongly inhibits this protein in a dose-dependent manner.
Treatment with vitamin C had the same effect on lipid profiles as inactivating ACSL4, and it strengthens the cells’ antioxidant capacity by activating molecular pathways governed by the master regulator of the oxidative stress response.
These findings prompted further testing in 12- to 16-year-old cynomolgus monkeys, which translates to around 40–50 years in humans. The monkeys received a daily dose of vitamin C at 30 mg/kg for 40 months. This treatment appeared not to cause any adverse effects.
However, vitamin C treatment affected ferro-aging processes. Monkeys that received vitamin C supplementation had reduced levels of ferro-aging-related genes across multiple tissues, including ACSL4; reduced age-related increases in plasma iron; decreased lipid peroxidation and MDA levels; and increased levels of the activated master regulator of the oxidative stress response.
Subsequent analysis of a broad spectrum of aging biomarkers across various tissues from aged cynomolgus monkeys receiving vitamin C suggested widespread geroprotective activity. The researchers reported improved aging hallmarks in cardiovascular tissues, lungs, liver, kidney, and pancreas, decreased adipocyte size in visceral fat, and neuroprotective effects.
The geroprotective effects of vitamin C in monkeys were also confirmed by epigenetic, transcriptomic, and metabolomic aging clocks as well as a structural MRI analysis, which showed that vitamin C supplementation helped alleviate age-related brain atrophy. The treatment also improved metabolic parameters of the animals and “reduced age-associated expansions in visceral and total fat area.”
A druggable target
As the authors summarize, this study identified “a specific, druggable pathway contributing to aging: an iron-triggered, lipid peroxidation-dependent process we term ferro-aging.” They also identify vitamin C as an inhibitor of this pathway with geroprotective potential.
This study was conducted on cell cultures and model organisms (mice and monkeys). Since monkeys are more closely related to humans than other model systems, vitamin C having positive effects in these animals makes it a promising candidate for human trials. However, since there is still a need to better understand the full impact of vitamin C on different aspects of health and to optimize its dosage and treatment timing; rigorous long-term safety evaluation is also necessary.
Literature
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