Review of the hallmarks of aging calls for drug trials to specify the level of benefit they will test, from target engagement to slowing aging across the body
Review of the hallmarks of aging calls for drug trials to specify the level of benefit they will test, from target engagement to slowing aging across the body
On September 11, Piotr Paweł Chmielewski and Bartłomiej Strzelec of Wroclaw Medical University published a review in International Journal of Molecular Sciences examining twelve hallmarks of aging, including the accumulation of DNA mutations and stem cell exhaustion. They propose treating these hallmarks as provisional causal modules: sets of interacting processes whose modification changes prespecified measures of bodily function through an identifiable mechanism.
In 2013, Cell published the hallmarks of aging framework. Biologist Carlos López-Otín and colleagues identified the first nine processes associated with aging and set three criteria: a hallmark appears with age, experimentally worsening it accelerates aging, and alleviating it slows aging.
The review authors argue that these criteria are insufficient until aging is defined and an outcome is chosen for evaluating the intervention. A change that appears with age may cause aging, result from it, or reflect the body's response to damage. The review assesses each hallmark through four questions: does it change reproducibly with age in human tissues; does modifying it change function or survival; does the effect persist under different conditions; and can it be measured and modified in humans?
For clinical trials, the review distinguishes six levels at which a drug can be claimed to provide benefit: target engagement (the drug modifies its intended process); a change in a biomarker (such as a substance in the blood); a change in the course of a disease; preservation of function (such as mobility or cognition); the body's response to and recovery from a challenge (such as vaccination or surgery); and slower aging across the body (sustained benefit across several systems).
“Trials should state which level they are testing and should not retrospectively raise the level of their claim after a favorable biomarker result.”
The review cites two trials of RTB101, a drug that inhibits mTOR, a protein that regulates cell growth. In both trials, the drug increased antiviral gene activity in older adults, indicating a biomarker change, but the clinical results differed. The earlier trial (phase 2b) enrolled people at increased risk, including those with chronic obstructive pulmonary disease and smokers: laboratory-confirmed respiratory infections occurred in 19% of participants receiving 10 мг daily and 28% of those receiving placebo. The subsequent trial (phase 3) excluded these two groups, and clinically symptomatic respiratory illness developed in 26% of participants receiving the drug and 25% of those receiving placebo. The review attributes the difference in trial outcomes to participant selection and the choice of outcome measure.
Senolytics, such as dasatinib combined with quercetin, selectively kill senescent cells, which have stopped dividing but remain alive and active. In a trial involving 60 postmenopausal women, the combination showed no difference from the control group in the primary outcome, a marker of bone breakdown. In an additional exploratory analysis, improvements in bone measures were concentrated in the third of participants with the highest blood levels of a marker of senescent cells. The review suggests that this treatment may require confirmation that a patient has a high burden of senescent cells.
The hallmarks influence one another: inflammation, for example, can impair stem cell function. The authors therefore conclude that the framework “should generate testable hypotheses at the system level rather than serve as a list of drug targets.”