One has to be cautious about studies in which metabolism is broken in some way, and symptoms of aging start to appear earlier as a result. Whether or not this has any relevance to normal aging is dependent on the fine details of the biochemistry involved, and can often be argued either way even by those with the most knowledge in the field. Aging is an accumulation of damage and dysfunction in cells and tissues. Many genetic alterations and toxins that disrupt cell metabolism will lead to damage and dysfunction, and thus conditions that appear similar to those of aging. But unless it is the same forms and distribution of damage, and it never is, there may well be little to learn that will help in treating aging.
In today’s research, the scientists involved find that deletion of TFAM from T cells in mice breaks mitochondrial function in a way that leads T cells to become highly inflammatory, pumping out signals that are known to increase the pace at which cells enter a senescent state. The mice exhibited raised levels of cellular senescence throughout the body, a characteristic attribute of older animals. Senescent cells contribute to aging via their own signaling that rouses the immune system to chronic inflammation and disrupts tissue function. The researchers tested a few interventions that partially reversed the harms done by this genetic modification, both of which are under investigation as therapies for aging, but the data from this study cannot indicate whether or not they would be useful in normally aged mice or humans. It is an example of producing a greatly exaggerated form of a dysfunction that does exist in normal aging, but to a lesser degree.
That aside, I think that this work does succeed in emphasizing the importance of mitochondrial function, chronic inflammation, and cellular senescence in aging. Scientific programs seeking to address the issue of mitochondrial decline in aging could certainly benefit with greater funding and support. Approaches to suppress chronic inflammation are popular and very well funded, but still somewhat stuck in the paradigm of blocking inflammatory signals, a strategy that has significant side-effects, rather than focusing on the root causes of overactivation of the immune system. At least we can say that work on clearing senescent cells from old tissues is finally forging ahead, better late than never.
Defective immune cells could make us old
Our T cells let us down as we age, becoming weaker pathogen fighters. This decline helps explain why elderly people are more susceptible to infections and less responsive to vaccines. One reason T cells falter as we get older is that mitochondria, the structures that serve as power plants inside cells, begin to malfunction. But T cells might not just reflect aging. They could also promote it. Older people have chronic inflammation throughout the body, known as inflammaging, and researchers have proposed it spurs aging. T cells may stoke this process because they release inflammation-stimulating molecules.
To test that hypothesis, researchers genetically modified mice to lack the TFAM protein in the mitochondria of their T cells. This alteration forces the cells to switch to a less efficient metabolic mechanism for obtaining energy. By the time the rodents were 7 months old, typically the prime of life for a mouse, they already appeared to be in their dotage. Compared with typical mice, the modified rodents were slow and sluggish. They had shrunken, weak muscles, and were less resistant to infections. Like many elderly people, they suffered from weakened hearts and shed much of their body fat. T cells from the altered mice poured out molecules that trigger inflammation, the team found, suggesting the cells could be partially responsible for the animals’ physical deterioration.
The scientists also tested whether they could slow the aging clock. First they dosed the mice with a drug that blocks tumour necrosis factor alpha (TNF-alpha), one of the inflammation-inducing molecules that T cells unleash; the treatment increased the animals’ grip strength, improved their performance in a maze, and boosted the heart’s pumping power. The researchers also gave the animals a compound that raises levels of nicotinamide adenine dinucleotide (NAD), a molecule that’s vital for metabolic reactions that enable cells to extract energy from food. NAD’s cellular concentrations typically decline with age, and the researchers found that ramping it up in the mice made them more active and strengthened their hearts.
T cells with dysfunctional mitochondria induce multimorbidity and premature senescence
The impact of immunometabolism on age-associated diseases remains uncertain. Here, we show that T cells with dysfunctional mitochondria due to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles chronic inflammation characteristic of aging (“inflammaging”). This cytokine storm itself acts as a systemic inducer of senescence. Blocking TNF-α signaling or preventing senescence with NAD+ precursors partially rescues premature aging in mice with Tfam-deficient T cells. Thus, T cells can regulate organismal fitness and lifespan, highlighting the importance of tight immunometabolic control in both aging and the onset of age-associated diseases.