Research Signal – Source date 2023-06-01
As people grow older, several chronic conditions can arrive together. Treating each one separately may mean more medicines, more interactions, and a greater daily burden. The geroscience hypothesis asks whether some of that burden could be reduced by targeting biological mechanisms shared across multiple age-related diseases.
The goal is not simply a longer life. Healthspan means the years spent without significant disease or disability. A drug that delayed several conditions while preserving mobility, cognition, independence, and quality of life would address a more practical question than whether it changed a single laboratory marker.
A June 1, 2023 publication in The Journals of Gerontology: Series A, Biological Sciences and Medical Sciences presents proceedings from a National Institute on Aging-funded workshop on this question. Its experts focused on three approaches: senolytics, NAD+ boosters, and metformin. They do not all act on the same biological process, and the evidence behind them does not answer the same question. Their comparison shows why an aging intervention must be judged by what it does for people, not only by what it changes in cells or animals.
One aging hypothesis, three very different interventions
The shared idea is that molecular pathways involved in aging also contribute to many common age-related diseases. If an intervention could modify those pathways, it might delay more than one disease at a time. This would differ from a system organized entirely around treating heart disease, diabetes, cancer, dementia, or frailty as separate problems.
The workshop proceedings describe that possibility as a research hypothesis, not an established treatment strategy. Senolytics try to remove certain cells that have entered a durable growth-arrested state. NAD+ boosters aim to alter a molecule central to metabolism and cellular signaling. Metformin begins with a familiar clinical use in glucose lowering, then becomes a candidate for broader aging research because of effects observed in experimental models and associations seen in human studies.
The same headline question therefore contains several smaller ones. Can a target be changed safely? Does the change improve a meaningful aspect of health? Does it work in the people most likely to benefit? And can the effect last long enough to alter the course of age-related disability?
Senescent cells are a removal problem, not just a target
Cellular senescence is one of the clearest examples of why a biological target cannot be treated as automatically harmful. Senescent cells have stopped dividing and can release inflammatory signals through what is known as the senescence-associated secretory phenotype. Their numbers tend to increase with age, and studies in mice have found benefits from clearing even a portion of them.
Senolytics are drugs intended to exploit the survival systems senescent cells rely on, so the cells are eliminated. Senomorphics take a different approach. They leave the cells in place but try to reduce the inflammatory secretions that may affect surrounding tissue. The distinction matters because removal and modification carry different biological consequences.
The proceedings describe early human findings in separate disease settings. A combination of dasatinib and quercetin was reported to clear senescent cells in patients with diabetic kidney disease. In patients with idiopathic pulmonary fibrosis, the same general senolytic approach was associated with improvement in measures of physical function. These findings are important signs that the biology can be studied in people, but they are not evidence that senolytics prevent multiple age-related diseases across the general population.
Senescence may also serve protective purposes. It can help stop cells carrying oncogenic damage from continuing to divide, which is one reason researchers have considered whether removing senescent cells could affect cancer risk. The workshop discussion also describes context-dependent effects on repair. Clearing transient senescent cells during skin injury delayed wound repair, while clearing them after bone fracture accelerated healing in mice. A cell that is harmful in one setting may be useful in another.
That makes safety more than a matter of whether a drug has been used before. Some potential senolytics are repurposed medicines with known clinical histories, but a drug used for a serious disease may require a higher safety threshold when offered to aging people without that disease. Researchers also need to know whether the relevant target is a high senescent-cell burden, a particular tissue, or a specific health problem. The prospect of selective removal depends on answering those questions without treating all senescent cells as disposable.
NAD+ is a metabolic lever with uneven returns
Nicotinamide adenine dinucleotide, or NAD+, is a molecule cells use throughout metabolism. Along with its phosphorylated form, NADP+, it helps carry electrons, supports the production of cellular energy, contributes to the synthesis of important molecules, and participates in signaling reactions. Cells must continually balance production and consumption to maintain these pools.
The proceedings describe declining tissue NAD+ levels as a feature associated with aging and disease, which gives researchers a reason to test precursor-based approaches. These include nicotinamide riboside and nicotinamide mononucleotide. But raising a molecule involved in many processes does not identify which health outcome will change, or whether a particular precursor will work in the same way as another.
Animal findings illustrate the uncertainty. Supplementing mice with nicotinamide riboside modestly extended life in some studies, while nicotinamide did not affect longevity in another. A larger study using genetically diverse mice also found no longevity effect from a lower dose of nicotinamide riboside. Other experiments targeting NAD+ breakdown or using disease models produced different results. The biological system can respond to the intervention without producing a consistent life-extension signal.
Human findings summarized in the proceedings are similarly mixed. Some studies reported modest changes in vascular function, blood pressure, inflammatory markers, kidney-injury outcomes, or muscle insulin sensitivity. Improvements in physical performance or metabolic measures were often modest or absent, although a study in people with mitochondrial myopathy found improved physical function after niacin increased NAD+ levels. These are different outcomes in different populations, not one general demonstration that NAD+ boosters improve everyday aging.
The gap between a biochemical change and a lived benefit is especially important here. A trial can show that a precursor raises NAD+ without showing that a person walks more easily, remains independent longer, or experiences better quality of life. Human studies also need enough time to reveal effects on chronic conditions and function. At the workshop’s point in time, the evidence supported continued investigation rather than a reliable healthspan regimen.
Metformin brings an established medicine into a new question
Metformin starts from firmer clinical ground. It is widely used to lower blood glucose and is generally recommended as a first-line treatment for type 2 diabetes and diabetes prevention alongside lifestyle changes. Its established role makes it attractive for aging research: researchers can investigate a familiar medicine while asking whether its broader effects reach beyond glucose control.
In experimental organisms, the proceedings summarize findings that metformin extended lifespan in worms and mice and improved several aging-related functional measures in mice. In people, observational studies associated metformin use with lower rates of cancer, cardiovascular disease, dementia, frailty, and all-cause mortality. Those observations help explain the interest in testing metformin for healthspan and frailty prevention.
The proposed biology is broader than blood sugar alone. Metformin activates AMP-activated protein kinase, an energy sensor involved in glucose and lipid metabolism. The proceedings also discuss effects involving mitochondrial respiration, liver metabolism, redox balance, incretin and bile-acid signaling, and possibly the gut microbiome. These mechanisms offer several routes by which the drug might influence aging-related processes, although they do not by themselves demonstrate a preventive effect.
The human observational findings also need to remain separate from a controlled demonstration of cause and effect. People who take metformin may differ from people who do not in ways that affect their health outcomes. The proceedings therefore present the associations as a reason for clinical trials, not as proof that metformin prevents age-related disease in people without diabetes. Its familiar status does not turn it into a universal longevity medicine.
The outcome that matters is life lived
The clinical destination for these approaches is not a single number. The workshop proceedings identify physical function, cognitive function, frailty, disability, patient-reported outcomes, and health-related quality of life as relevant domains. Together, they describe whether a person can continue doing the activities and roles that make daily life workable and meaningful.
That standard changes how the interventions should be compared. Clearing senescent cells might matter if it produces durable improvements in function without compromising repair or other protective roles. Changing NAD+ metabolism might matter if a measurable biochemical shift translates into better physical or cognitive performance in a defined group. Metformin might matter if its experimental and observational signals become a safe, reproducible reduction in frailty or disability in an appropriate population.
Who receives treatment is part of the scientific question. The proceedings raise whether senolytics would help all aging people or mainly those with a high burden of senescent cells. Similar selection questions may arise for the other approaches, because the biological state of an older adult is not uniform. A therapy aimed at a shared mechanism may still need to be tailored to a person’s conditions, risks, and goals.
The studies must also show that any benefit outweighs added harms and treatment complexity. Older adults often live with multiple conditions, so a new therapy should not worsen existing medical problems or create another layer of polypharmacy. Larger pragmatic trials will be needed to establish effects beyond small early-phase studies and to test outcomes that matter outside a tightly controlled research setting.
What this could change
The most meaningful prospect is not a promise of rejuvenation. It is the possibility that a carefully selected treatment could delay several age-related conditions at once and help an older person retain the ability to function independently for longer. That would give healthspan research a concrete public purpose: more time able to live, move, think, and participate without significant disease or disability.
For that possibility to become real, one or more approaches would need to show durable functional benefits, acceptable safety, and a clear way to identify the people most likely to benefit. Only then might care gradually shift from managing age-related diseases one by one toward addressing shared biological processes. The proceedings provide reasons to investigate that future, but not evidence for a universal preventive pill or a demonstrated reduction in medication burden.
Key Sources
- Primary source: Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop.
DOI or Journal Page · Peer-Reviewed Paper · 2023-06-01
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