Longevity | Toward a Model of Age, Aging & Therapeutic Rejuvenation

Session Focus

Gulfo opened with two women, both 80 years old. One travels, walks several miles a day and remains deeply connected to her community. The other struggles with mobility, needs help with daily tasks and has become increasingly frail. Genetics, lifestyle, environment or luck?

Her framing: medicine has treated the consequences of aging for generations, and the question now is whether the biology of aging itself can be treated.

She then asked the room for a show of hands on whether, within the next 20 years, there will be a medicine that treats the underlying aging process rather than its consequences, and told the audience to remember their answer because she would ask again at the end.

How the Panel Defines Longevity

Kristen Fortney PhD anchored her definition in the distinction between lifespan and healthspan. In the US there is roughly a 20-year gap on average, meaning the final two decades of life carry an increasing burden of chronic disease. For her, the goal is not reaching a ripe old age but aging well, healthy and functional.

Raj Panjabi MD drew on a career spanning clinical medicine and the National Security Council, where he worked on public health crises before joining Flagship Pioneering. His lesson from both: the greatest victories in health are when suffering is avoided altogether.

What excites him about this moment is the convergence of computational and biological science. The implication is that the field need not wait for a heart attack to strike, for a cancer to grow large enough to detect, or for memory loss to signal dementia before acting.

Elisabeth Roider MD, PhD, a dermatologist and physician scientist who co-founded one of the first venture studios and funds in the longevity space six years ago, framed it as a third wave in medicine. Acute care came first, fixing what had already happened. Chronic disease management came second. What is now possible is examining the molecular level, which is primary prevention in the true sense: seeing disease before it becomes clinically visible.

David Scadden MD, a hematologist-oncologist and stem cell biologist who founded the Harvard Stem Cell Institute and the MGH Center for Regenerative Medicine, named a specific organ he believes is coming into focus as central to aging, with some irony, since it is also the body’s fastest-aging organ: the thymus.

The Thymus Findings

Scadden explained why the organ has been overlooked. It sits between the sternum and the heart, begins deteriorating in childhood, and involutes markedly at puberty as it converts to fat. Because of that it has been considered largely vestigial in adults, to the point that thoracic surgeons commonly remove and discard it when it obscures the operative field.

During COVID, unable to enter the laboratory, his group turned to Mass General Brigham’s clinical databases and associated biobanks. They examined thousands of middle-aged patients who had undergone chest procedures, comparing those whose thymus was removed against those whose was not.

Normalized for diagnosis, the effect on all-cause mortality was striking. Patients who lost the thymus showed roughly a 2.4-fold increase in relative risk, with a hazard ratio around 1.6, driven largely by increased incidence of and death from cancer, and some deaths from autoimmunity.

That led to a second question: in patients who retain the organ, can its vigor be measured? The group modified a blood test to run on banked samples. Patients with a cancer diagnosis whose thymus activity fell below the mean showed different outcomes for some cancers, different rates of accumulating new genetic changes within those cancers, and different overall responses to checkpoint inhibitor therapy.

Work by a Brigham colleague approached the same organ radiographically, using machine learning on chest CT scans to show that thymic intactness associates with longevity, with cardiovascular and cancer outcomes, and with checkpoint inhibitor response.

Scadden’s assessment: the associations are now strong, mechanistic understanding is growing, and this long-ignored organ may prove central to protecting against at least some consequences of age.

How You Would Know It Worked

Asked how restoration of an aging thymus could be shown to change the course of aging rather than simply improve immunity, Scadden began by adjusting the premise. Aging is modulable, and human longevity has already shifted over recent decades.

His proposed clinical test is concrete. Because the thymic activity indicators correlate with response to checkpoint inhibitors, a trial could enroll patients with low levels, attempt to raise them, and measure whether checkpoint inhibitor response changes.

Simpler readouts are also available. Vaccine response is age-dependent in known ways, including the two-dose influenza requirement above a certain age. That makes it possible to measure age-related risk through straightforward blood parameters and test whether an intervention modifies them.

Evidence Thresholds for the Clinic

Fortney described what convinces academic scientists versus what should convince a company.

In academia the ultimate test is whether the mouse lives longer. Making an animal live shorter, or affecting a particular tissue or functional readout, is usually easy. Making an animal live substantially longer is hard. A growing list of interventions does achieve it, and confidence rises when animals not only live longer but show delayed onset of multiple diseases and improved function.

The harder question is translation. She was careful here: mice have a poor translational record in some areas and a good one in others, with Alzheimer’s the classic example of poor translation.

Her company’s answer is to work from large human datasets, on the logic that there are eight billion human aging experiments running concurrently. That has meant substantial investment in building biobanks with longitudinal data.

The Translation Gap

Roider named the field’s central practical problem plainly. The ideas are there and the science is strong, and moving any of it to a patient remains extraordinarily difficult.

Part of the reason is structural: aging is not classified as a disease, which means it attracts little government funding, leaving the work dependent on private capital.

On Supplements

Asked about the consumer longevity market, Fortney was dry. Most of it is safe enough. Her test for whether anything in it works: if any of these products had a large effect, a handful of people taking them would have made that obvious by now.

The Second Show of Hands

Gulfo closed by putting her opening question to the room again. Fewer hands went up than the first time.

Key Takeaways

1. Healthspan, not lifespan, is the target. The 20-year US gap between the two is what the field is trying to close.

2. The thymus may be central and has been discarded. Removal associated with a 2.4-fold increase in relative mortality risk.

3. Thymic activity is measurable in blood and on CT, and correlates with cancer outcomes and checkpoint inhibitor response.

4. A clinical test already exists in outline. Raise thymic activity in low-level patients and measure immunotherapy response.

5. Mouse longevity is necessary but not sufficient. Translation records vary sharply by disease area.

6. Aging is not classified as a disease, which removes government funding and shifts the burden to private capital.

7. The room grew more skeptical, not less. Fewer hands went up on the closing question than the opening one.