Aging occurs as damage outpaces weakening defenses, with inflammation as a response: the model proposed by Luigi Ferrucci, scientific director of the US National Institute on Aging
Aging occurs as damage outpaces weakening defenses, with inflammation as a response: the model proposed by Luigi Ferrucci, scientific director of the US National Institute on Aging
On October 28, the Decoding Longevity channel posted an interview with Ferrucci about inflammation, muscle mitochondria, and the vicious cycle of tissue aging.
Ferrucci once considered inflammation a cause of aging. In his 1999 study, people aged 71 and older in the highest third of interleukin-6 levels, an inflammatory signaling protein, were 1,76 times as likely to lose mobility as those in the lowest third. “I thought I would win the Nobel Prize: the association was so strong that I had found the cause of aging.”
He now views aging as the balance between two processes: molecular damage accumulates, while evolved defenses counter it by repairing DNA and correcting misfolded proteins. These defenses weaken with age, allowing damaged molecules to accumulate. For example, mitochondrial DNA, normally hidden from the immune system inside mitochondria, escapes. The body has not learned to recognize these molecules as “self,” interprets them as invading viruses or bacteria, and mounts an inflammatory attack. Inflammation is intended to be a brief response and temporarily suppresses protein synthesis. But the damage continues, prolonging inflammation, which interferes with the replacement of worn proteins and prevents tissue renewal. Ferrucci says the CANTOS trial cast doubt on inflammation as a common cause of disease: an antibody against interleukin-1β (150 mg) reduced the risk of recurrent cardiovascular events but did not prevent other diseases.
Ferrucci describes a “gap” between cell biology and the whole organism: how cellular changes lead to a loss of function in the organism remains unknown. He calls the conclusion that “one organ is aging faster than another,” based on faster epigenetic age “clocks” (which use DNA marks) or protein age “clocks,” “very superficial thinking.” He accepts that these clocks may be associated with functional decline but wants to measure the decline itself.
In the Baltimore Longitudinal Study of Aging, researchers measure muscle mitochondrial energetics without a biopsy: an MRI scanner shows how quickly mitochondria replenish phosphocreatine, an energy reserve, after exercise. This measure is associated with walking speed and, to Ferrucci’s surprise, with dementia: a value one standard deviation higher was associated with a 52% lower risk of mild cognitive impairment or dementia (469 participants, an average of five years of follow-up, 23 cases). Ferrucci explains that muscles, the brain, and the kidneys consume large amounts of oxygen and are the first to suffer when energy is scarce, so muscle provides information about the health of the whole organism.
Mitochondria are part of a vicious cycle that Ferrucci and his colleagues described in Cell Metabolism as a conceptual model with no single starting point: the collagen framework surrounding cells becomes denser and impedes capillary growth, tissues receive too little oxygen, mitochondria produce less energy than repair requires, and cells become senescent and release enzymes that further densify the framework. According to the paper, the energy shortage also weakens defenses, allowing damage to accumulate.
His group tested the effects of oxygen deprivation in mice (npj Aging), building on an earlier finding: age-related DNA marks in immune cells accumulate at sites where regulators of the response to oxygen deprivation act. For one month, oxygen levels in the chamber air fluctuated from 21 to 5% for 8 hours a day. The epigenetic age of the heart, spleen, and lungs in 23-month-old females increased by 2,9–5,3 months, as measured by Universal Clock 3.
Ferrucci plans to test this cycle in humans in the PRISM study.