The tree · branch 5 of 8

Energy and fuel sensing

The cell's power plants, which fail with age, and the pathways that sense how much food is coming in, which run wrong with age and are the target of the drugs most often said to slow ageing.

Of the twelve published hallmarks of ageing, this branch groups 2: the pathways that sense food running wrong and the cell's power plants failing.

Where this branch stands

required: the year cannot arrive until this branch is handled; handled when 2 treatments are in the clinic

2028handled, in the middle run
1of 8 in the clinic already
in clinical usefurthest stage reached

One treatment under this branch is in the clinic already (a weight-loss drug is approved to prevent heart attacks and strokes in people without diabetes, 2024); the branch counts as handled when one morereaches it, and in each run of the model that year is drawn from the ranges below. Across all the runs, the middle year this branch is handled is 2028.

8 treatments and tools

listed by how soon each could reach its next rung

A weight-loss drug is approved to prevent heart attacks and strokes in people without diabetes In clinical use in the clinic since 2024
Next rung within 1 to 5 years. The GLP-1 drugs (semaglutide, sold as Wegovy and Ozempic, and their successors) copy a gut hormone that tells the body it has eaten, and they act on the same fuel-sensing pathways the ageing field has studied for decades.
A drug is approved to make dogs live longer Idea only clinic likely 2028, 2027 to 2032
Next rung within 1 to 5 years. Dogs share our homes, our food and many of our diseases, and they age fast enough that a lifespan trial finishes in years, not decades.
A drug that renews the cell's power plants improves muscle in older people First human clinic likely 2039, 2031 to 2085
Next rung within 5 to 20 years. Cells clear out worn mitochondria (their power plants) and build new ones, and both slow with age, so old muscle runs on tired machinery.
A rapamycin-type drug improves an age-related measure in older people First human clinic likely 2039, 2031 to 2080
Next rung within 5 to 20 years. Rapamycin and its relatives damp down a pathway (mTOR) that senses how much food is coming in, and they are the drugs with the strongest record of extending life in animals.
A supplement that raises a cell's NAD improves an age-related function in a controlled trial First human clinic likely 2042, 2032 to 2090
Next rung within 5 to 20 years. NAD is a molecule every cell uses to turn food into energy and to run its repair enzymes, and its level in tissues falls with age.
Fresh mitochondria are transplanted into a person's failing tissue First human clinic likely 2045, 2033 to 2095
Next rung within 5 to 20 years. Mitochondria are the cell's power plants, and they fail with age; one way around that is to put fresh ones in.
A drug makes people live longer in good health Shown in animals clinic likely 2045, 2034 to 2095
Next rung within 5 to 20 years. A pill that slows ageing itself, rather than treating one disease, so that the people who take it live longer and stay well longer.
Metformin delays age-related disease in people who do not have diabetes Shown in animals clinic likely 2043, 2036 to 2100
Next rung within 5 to 20 years. Metformin is a cheap diabetes pill taken by hundreds of millions of people, and it acts on the pathways that sense how much fuel a cell has.

What would move this

the next test each treatment needs, and the branch's own line

A controlled trial in people in which a drug that acts on these pathways keeps the people taking it free of age-related disease longer than those on placebo, by the margin the trial was designed to detect.

A weight-loss drug is approved to prevent heart attacks and strokes in people without diabetes Next rung: in wide use. Available to the general public in at least one country without joining a trial, and taken up by many people. Settled by the peer-reviewed trial report; the regulator's approval record; published uptake figures for the wide-use rung.
A drug is approved to make dogs live longer Next rung: shown in animals. Shown to work in a living animal, in a peer-reviewed report. Settled by the regulator's own approval record; for the first rung, the peer-reviewed report of the trial.
A drug that renews the cell's power plants improves muscle in older people Next rung: in clinical use. A regulator somewhere has approved it, or it is in routine use in a named clinical setting, so a doctor can give it to a patient outside a trial. Settled by the peer-reviewed trial report; the regulator's approval record for the clinic rung.
A rapamycin-type drug improves an age-related measure in older people Next rung: in clinical use. A regulator somewhere has approved it, or it is in routine use in a named clinical setting, so a doctor can give it to a patient outside a trial. Settled by the peer-reviewed trial report; the regulator's approval record, or a named clinical setting's published practice, for the clinic rung.
A supplement that raises a cell's NAD improves an age-related function in a controlled trial Next rung: in clinical use. A regulator somewhere has approved it, or it is in routine use in a named clinical setting, so a doctor can give it to a patient outside a trial. Settled by the peer-reviewed trial report; the regulator's approval record for the clinic rung.
Fresh mitochondria are transplanted into a person's failing tissue Next rung: in clinical use. A regulator somewhere has approved it, or it is in routine use in a named clinical setting, so a doctor can give it to a patient outside a trial. Settled by peer-reviewed reports; the trial registry; the regulator's approval record for the clinic rung.
A drug makes people live longer in good health Next rung: first human. At least one person has had it, with a public record of that result. Settled by the peer-reviewed trial report, and the regulator's approval record if it comes to that.
Metformin delays age-related disease in people who do not have diabetes Next rung: first human. At least one person has had it, with a public record of that result. Settled by the peer-reviewed trial report; the trial registry; the regulator's approval record for the clinic rung.

Its history

the handled year, computation by computation

The year was first computed on 17 October 2026, with this branch handled in the middle run by 2028. Every estimate under it is still a first pass. From the second computation on, this section charts the branch's handled year run by run, so a reader who sees the year at the top move can tell which branch moved it.

What the story so far says about it

the promises, the self-experiments and the papers that bear on this branch

Promised, in public

9 August 2022Nir Barzilai: A six-year trial of metformin against ageing in more than three thousand people aged sixty-five to seventy-nine at fourteen centres, starting in 2022, and by his own account promised for each year since about 2015. Verdict: missed.
26 September 2022Charles Brenner: No date or result: a critique holding that ageing is not a disease, that getting healthier is not age reversal, and that the book's claims of reversal in people are stories, not findings. Verdict: cannot be settled.
29 February 2024David Sinclair: A result already in hand: that a supplement combining a booster of the cell-energy molecule NAD with a drug that kills worn-out cells had been proven, in a trial, to reverse ageing in dogs. Verdict: missed.
26 February 2025Loyal: The two remaining sections of the conditional-approval application for LOY-002 complete by the end of 2025, and, in the same post, an approved longevity drug for millions of dogs within the next year. Verdict: missed.

Tried on themselves, in public

2006David SinclairRunning. A claim about one person is a story, not a record, and it moves nothing on this branch.
2010Mikhail BlagosklonnyEnded. A claim about one person is a story, not a record, and it moves nothing on this branch.
2018Peter AttiaRunning. A claim about one person is a story, not a record, and it moves nothing on this branch.
2021Bryan Johnson, BlueprintRunning. A claim about one person is a story, not a record, and it moves nothing on this branch.

On the record

9 July 2026Changes in Semaglutide Fills Following Expanded FDA and Medicare PoliciesScannell and 4 others.
22 April 2021Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic womenYoshino and 10 others.
12 September 2024Metformin decelerates aging clock in male monkeysYang and 43 others.
9 February 2023Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trialWaziry and 21 others.
7 October 2024Implausibility of radical life extension in humans in the twenty-first centuryOlshansky and 3 others.
4 April 2025Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial resultsMoel and 6 others.
29 March 2018Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adultsMartens and 7 others.
24 December 2014mTOR inhibition improves immune function in the elderlyMannick and 11 others.
3 January 2023Hallmarks of aging: An expanding universeLópez-Otín and 4 others.
6 June 2013The Hallmarks of AgingLópez-Otín and 4 others.
11 November 2023Semaglutide and Cardiovascular Outcomes in Obesity without DiabetesLincoff and 16 others.
3 May 2016The dog aging project: translational geroscience in companion animalsKaeberlein and 2 others.
8 July 2009Rapamycin fed late in life extends lifespan in genetically heterogeneous miceHarrison and 13 others.
12 May 2022Foreword to the Aubrey de Grey and Charles Brenner debate (Let's Talk Longevity newsletter)Gobel.
15 February 2017Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injuryEmani and 4 others.
October 2019TAME: A Genuinely Good Use of 75 Million DollarsGrey.
15 June 2004Escape Velocity: Why the Prospect of Extreme Human Life Extension Matters NowGrey.
2 February 2022An open science study of ageing in companion dogsmembers).
June 2016Metformin as a Tool to Target AgingBarzilai and 3 others.
31 July 2014Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controlsBannister and 7 others.
4 July 2026The TAME Trial (Targeting Aging with Metformin)Research.

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