A landmark paper in 2013 gave researchers a checklist for why bodies wear out. It named nine kinds of biochemical change that occur in every organism that ages, and they have been used ever since to organize the science of aging. In January 2023 the paper’s authors updated the list and added three more.
The hallmarks fall into three groups. Primary hallmarks are the root causes of cellular damage. Antagonistic hallmarks are the compensatory responses to that damage. Integrative hallmarks are what the first two add up to: further breakdown in how the body works.
To make the list, each hallmark was supposed to meet two tests. Raising it experimentally speeds up aging, and correcting it slows normal aging and extends healthy lifespan. The second test is the weak one. For many hallmarks, science has not yet found a workable way to make the correction in living organisms.
The primary damage
Genomic instability comes first. Oxidative stress and environmental factors damage DNA, and cells run repair systems all the time, but the repairs are imperfect, so damage builds up. Several review articles have shown that poor DNA repair causes premature aging and that better repair is linked to longer life. The same instability sits at the center of cancer and drives some neurodegenerative diseases, among them amyotrophic lateral sclerosis.
Telomeres cap the ends of chromosomes. Leonard Hayflick showed that normal human fetal cells divide 40 to 60 times in culture before they enter senescence, and each division shortens the telomeres a little. Division stops when they reach a critical length. An enzyme called telomerase rebuilds telomeres in gametes and stem cells, and in mice with a telomerase deficiency, reactivating it reversed premature aging.
Epigenetic changes come next. Only some genes are active in a cell at a given time, and histones decide which. With age, the pattern slips: useful genes switch off and unneeded ones switch on. Sirtuins, proteins that help keep unneeded genes off, depend on NAD, and cells hold less of it as they age.
Proteostasis, the upkeep of every protein in its proper shape, also declines. Damaged and clumped proteins pile up with age. Caloric restriction and the drug rapamycin can slow that loss, both by inhibiting the mTOR pathway.
Responses and fallout
Nutrient sensing runs through mTOR as well. When food is plentiful, mTOR drives growth. When nutrients run low, the AMPK receptor switches it off to save resources. Forcing the pathway on in grown mice led to faster aging and more cancer, while inhibiting it, through dietary restriction or rapamycin, ranks among the most robust ways to lengthen life in worms, flies and mice.
Mitochondria lose efficiency with age. Why is still unclear, though suspects include damage to mitochondrial DNA, oxidized proteins and failing quality control. Faulty mitochondria interfere with signaling inside the cell and set off inflammation.
Cellular senescence is what happens when a cell leaves the cycle without dying and goes dormant. Senescent cells become more common with age and secrete inflammatory markers, and clearing them has been found to delay the onset of age-related disorders.
Whole-body failure
Stem cells are the body’s replacements, and their numbers and speed of division fall over time. Rejuvenating them has reversed some effects of aging in whole organisms.
Cells also talk to each other through molecules released into the blood, and that conversation changes with age. One result is “inflammaging,” a chronic low-grade inflammation that wears out the immune system and damages healthy tissue. Senescent cells add to it through a set of secreted molecules known as SASP, which pushes neighboring cells into senescence.
Twelve and counting
The 2023 review added macroautophagy, chronic inflammation and dysbiosis, for a total of 12 proposed hallmarks. Others have been suggested beyond those. One proposal holds that endogenous retroviruses in the human genome can wake from dormancy and drive senescence and tissue aging, and that neutralizing antibodies can block this.
Consult your doctor for medical advice.
