The Broad Prevalence of Bad Epidemiological Data for Exceptional Human Life Expectancy

In recent years, greater attention has been given to efforts that push back against the present broad acceptance of established data on human life expectancy, particularly for the oldest surviving cohorts. It has been suggested, and the evidence for this assertion is broadly supportive, that the published data for exceptional longevity is largely of poor quality, and much of what has been hyped over the years (such as Blue Zones or Jeanne Calment's alleged life span of 122 years) is simply not real.

What is observed in the data is a selection effect for error, fraud, and outright falsehood that grows stronger at advancing ages. We should be quite confident that a small number of humans can survive into their 110s, as individual cases have been well vetted, but we should be much less confident about the accuracy of demographics of survival much past age 90.

Does any of this really matter? From the perspective of building therapies to treat aging, I think probably not. It doesn't affect the need for better ways to measure biological age than exist at present, and it doesn't change the list of programs and targets that should be undertaken to produce potential rejuvenation therapies. People do get somewhat up in arms about the demographics of aging, but it seems a tempest in a teacup to me, somewhat irrelevant to the real issue of making progress in the treatment of aging as a medical condition. Other people may see it differently, of course.

How long can humans live? We simply don't know

Many errors are undetectable and, therefore, we do not know their underlying frequency. This has prompted a rather absurd response from demographers, who say that, sure, some errors occasionally escape detection, but these errors must be rare. I usually ask them: if you cannot detect particular errors, how do you know that they are rare? The core problem is that age relies on one measurement system: paperwork. If a person's paperwork is consistent but wrong, there is no reproducible way of knowing. You often see a famous case discussed, the details exhaustively validated and all of the paperwork examined. But after decades, the case turns out to be false. It has passed every test that demography has, and it is still wrong.

I did not just observe this in individual cases. I found it in entire populations. In Greece, for example, at least 72% of centenarian records were cases of pension fraud. The person was left alive on paper while their younger relatives collected the pension cheques. That was the secret to longevity in Greece, and nobody in demography saw it for decades.

There are several overlapping error processes. Pension fraud is one. Clerical error is another, and that can be undetectable. People who have paperwork with incorrect details often do not know, because literacy rates a century ago were low. Some people purposefully increase their age to escape military service, others to marry or work earlier when they are young, and some just inherited paperwork from older relatives because it was easier than travelling or paying to register a new birth. Then there are identity substitutions. Imagine a room with 100 people over 100, all holding valid paperwork. Replace one of them with a younger sibling. How do you detect the swap? The paperwork is real. The person knows enough about their sibling to answer questions.

Even if you understand the social and administrative context, there is still no reproducible method to test whether the age on a person's paperwork is correct. That is the central issue. There are also broader patterns. Extreme longevity often appears in places with weak record systems, low incomes and low historical levels of birth certification. That pattern runs against expectations if the signal were biological.

The mathematical process for small errors to dominate at very old ages is counter-intuitive but simple. Normally, rare errors can be ignored. But in this case, they grow non-linearly. Take a large population at age 50. Introduce a small number of people whose true age is younger than this recorded age. These individuals are biologically younger than the rest, so they die at lower rates as the cohort ages. Each year, the proportion of people with an error in their records increases because people with an inflated age are more likely to survive than are people with accurate data. Even with tiny starting error rates, you can end up with a population that has a 100% rate of errors at very old ages.

This is a universal problem. Five to ten per cent of people in the United States misstate their age in the census. Often, they simply do not know. Nearly one-quarter of the world's children still do not receive a birth certificate. Add that to the slow historical roll-out of birth registration and you get widespread uncertainty. There has been a 40-year debate about whether there is a limit to human lifespan. Both sides seem to be wrong, and the data seem to be junk. Demographers have been drawing shaky inferences from bad data for decades.

IFNAR1 in Mitochondrial Dysfunction in Parkinson's Disease

Mitochondrial function is clearly important in the development of Parkinson's disease. The mutations associated with increased risk of Parkinson's are related to mitochondrial quality control and function. Greater mitochondrial dysfunction makes the dopaminergic neurons most vulnerable to Parkinson's pathology that much more vulnerable, though it is an open question as to whether this is more a matter of disrupted energy metabolism or increased inflammatory signaling, both of which result from the presence of failing mitochondria in cells. Here, researchers report that expression of IFNAR1 is reduced in Parkinson's disease. That reduced IFNAR1 expression causes mitochondrial dysfunction via impairment of the quality control mechanisms of mitophagy, the same sort of issue as accelerates Parkinson's in genetic cases. Establishing whether or not this discovery may lead to a viable therapy to delay onset and progression of Parkinson's disease via increased IFNAR1 expression will require further research and development.

Dysregulated interferon-alpha/beta-receptor 1 (IFNAR1) signaling was recently identified to contribute to the development of sporadic Parkinson's disease (PD) into PD with Dementia (PDD). The molecular, cellular, and phenotypic impacts of brain IFNAR1 loss in aging have not been explored in vivo, which may reveal novel disease mechanisms and therapeutic targets. Baseline IFNAR1 expression varies among major brain cell types, including neurons and astrocytes, and is differentially affected in PD and Lewy Body Dementia patients compared to unaffected controls.

Neuron- and astrocyte-specific transcriptomic and proteomic alterations in IFNAR1 knockout mice implicate mitochondrial defects, defective mitophagy, and synergistic dysfunctional neurotransmission upon IFNAR1 loss, leading to glucose hypermetabolism measured by functional metabolic analysis. Consequently, IFNAR1 knockout mice exhibited PDD-like pathogenesis, including dopaminergic cell loss in the substantia nigra, cortical neurodegeneration, Lewy-body-like inclusions, neuroinflammation, and progressive PDD-like behavior deficits. Brain cell-specific IFNAR1 loss examined in vivo revealed delayed but distinct development of PDD-like phenotypes, where neuropathology, motor, and cognitive behavior deficits were recapitulated only in mice lacking neuronal IFNAR1, and behavior resembling neuropsychiatric abnormalities recapitulated only in mice lacking astrocytic IFNAR1.

Link: https://doi.org/10.1186/s12929-026-01257-8

Dividing Current Efforts to Treat Aging Between Two Camps: Senescent Cells and Metabolic Manipulation

It seems perhaps overly reductionist to summarize the panoply of current efforts to treat aging into two camps of (a) things that affect the burden of cellular senescence and (b) things that affect metabolism. One has to cut out or diminish the importance of a fair number of line items that may be useful irrespective of their effects on cellular senescence. An increased burden of cellular senescence is only one of the major issues that drive aging. Nonetheless, that is the approach to categorization taken in this review paper.

Aging is a complex biological process characterized by progressive functional decline, driving the incidence of age-related diseases such as neurodegeneration, metabolic disorders, and cardiovascular diseases. Therapeutic strategies targeting aging hallmarks can delay aging and mitigate disease risk. Emerging interventions focus on modulating core aging mechanisms, including cellular senescence, metabolic dysfunction, epigenetic alterations, and mitochondrial impairment, etc.

Recent advances have focused on three strategies: senolytics (eliminating senescent cells, e.g., dasatinib + quercetin), senomorphics (inhibiting the senescence-associated secretory phenotype, e.g., rapamycin), and senoreversion (rejuvenating senescent cells via epigenetic reprogramming). Additionally, metabolic interventions such as caloric restriction mimetics (e.g., spermidine, α-ketoglutarate, ergothioneine) enhance mitochondrial function, activate autophagy, and reprogram energy metabolism, demonstrating lifespan extension and healthspan improvement in preclinical models. Collectively, these approaches hold promise for delaying aging and alleviating age-related pathologies, facilitating the transition to precision longevity medicine.

Link: https://doi.org/10.1038/s41392-026-02662-z