Updates to the LongevityPlaybook 14: The Great Age Reboot is getting nearer

Update #4 Spring Summer 2025

In this week’s blog we will start a mult-part series on updates to the Longevity Palybook 14 (interrupted by a few answers to questions readers or this blog or subscribers to our free newsletter at LongevityPlaybook.com have asked repeatedly). I am borrowing the Diamondis format of the Update Scientifically and then WHY It Matters: , as this format seems to be a great update set that the test group of LP.com Newsletter readers like. To give new readers a flavor or summary of the Great Age Reboot Longevity 14 concept:

Over the last 170 years Life expectancy at birth for women in the USA has increased from 42 to 81 years–in a relatively straight line of about 2.5 year gain every ten years. Initially due to improvements in sanitation and infant health, and later in management of chronic diseases like high blood pressure, and diabetes.

But we are likely to get a 30 year exponential jump in the next decade—you’re about to be able to live longer and younger than ever before---this jump in how long you will live is due to exponential progress in 14 areas of mechanisms of aging research—each of which has already proven to change aging in at least 2 animal species.

I like the understanding of exponential in terms of time and cost for the SNPs of the human genome—10 years and 3 billion US dollars in 1991-2001 money and time, now 6 hours and 40 dollars in today’s US dollar.. a 12,000 fold reduction in time and a 8000 fold reduction in costs, with better accuracy. Imagine if that happened in cars – a car for under $120 dollars!!! That exponential change in time and cost explains why research into the mechanisms of aging can happen so fast—and why:

We expect with at least an 80% probability that one of these 14 areas of research in aging mechanisms will break through and allow you to function as a 40 year old at calendar age 90. Here are the 2 of the 14 updated—the ones I expect to hear breakthroughs continually, but all 14 are still in play—we will keep updating these:

· Mitochondrial Restoration and Elimination of obesity and its consequences with white to brown fat transformation and GLP-1’s with resistance exercise

Update 10/1/24 : Prices for obesity prevention and treatment (and opioid and nicotine and alcohol prevention and treatment with GLP-1’s are $95 a month retail in UK versus $250 in Canada and $1100-$1300 in USA. But Nova Nordisk CEO (Semaglutide) at Senate hearing on 9 25 24 promised much lower costs in USA and Eli Lilly is already at $399 a month.

Why It Matters: Clearly selling 10 times the starting dose at $95 a month in UK means costs for preventing and treating these addictions and their consequence will be available and reduce the effects of obesity and related conditions like diabetes, heart disease 6 cancers, osteoarthritis and dementia soon, and radically reduce disability rates. Wipe out obesity and opioids and disability free life expectancy expands 6 years in USA (make your RealAge 6 years younger).

Update 5 1 25: Now we have randomized controlled trial that one or the other of these meds decreases risk of heart attacks, strokes, dementia, kidney failure, liver failure, cancers, much osteoarthritis (the leading cause is obesity) and even chronic lung disease (https://www.frontiersin.org/journals/pharmacology/articles/ 10.3389/fphar.2023.1102792/full). I am told it is $50 a month in Great Britain, and available to all in NHS. Maybe the Trump Tarriff deal with Great Britain should have included re-importing Mounjaro without even having to ship it to the UK first. Moreover if this restores mitochondrial energy production, we would be able to have the energy level we had when we were teenagers. Okay, when will it get inexpensive enough to hand out like we do statins for preventing aging to all over calendar age 50. Sign me up as soon as data on 10 year risks are available for people without type2 diabetes.

Update 5 1 25: At the University of Alabama remarkable progress in rejuvenating mitochondria with a natural product (not disclosed that I can determine: (DOI: 10.1038/s41419-020-2649-z; DOI: 10.1016/j.mito.2023.02.012; doi: 10.1038/s41419-018-0765-9). The data in the articles and the website indicate remarkable skin and hair rejuvenation from topical application of a small molecule product (not needing extensive FDA approved testing and safety and efficacy data).

Why It Matters:To my reading of these article and review of the website, such a small molecule can be administered systemically, and return your energy level (if mouse data pertains) to that of someone at least 12 years younger (make your RealAge or ActualAge 12 years younger) than your calendar age.

For skin and hair, this mitochondrial rejuvenator is available now at Target..Revive+1 for $19.99 for a month. I’d like the data on mitochondrial rejuvenation validated by another Academic research group independent of the U of Alabama group, but am trying on my left arm while right arm skin and hair gets the usual soap, water and sun block. Pictures taken. That’s how good the data are –and yes if really a small molecule some should get absorbed.

· Senolytics incuding Therapeutic Plasma Exchange (The Harvesting of Old Cells and proteins that Make Neighbors Old) Now with Senorejuvenators.

Update 10/1/24 : Senolytics are a class of drugs which selectively kill or induce the clearance of senescent cells, hopefully leading to their replacement in the tissue and the suppression of the bystander effect. Senostatics are a similar class of drugs but, instead of directly clearing senescent cells, they act by blocking the bystander effect and the spread of the senescent phenotype.

And therapeutic plasma exchange is a form of senolysis without the senolytics. Senolysis or tissue plasma exchange may make you younger.

Classic senolytics, the stimulation of apoptosis in senescent cells, has been studied for the last decade with results that remain mitigated. Effective senolytics are still being sought but other approaches to blocking the impact of pathologic cell signaling, such as senostatics and senomorphics, are also being evaluated in combination with other treatments for an array of diseases.

It may be that the best way to remove senescent cells is to reenable healthy cell apoptosis and replacement is by repairing short telomeres, which activates senescence.

Particularly promising is evidence that Therapeutic Plasma Exchange: One of the tenets of healthy living comes down to the idea of substitutions. If you can sub in good things for bad ones, you’ve got a fighting chance to get rid of destructive habits and form beneficial ones. Sub in crunchy veggies, sub out chips. Sub in fiddling with a rubber band, sub out fiddling with a cigarette. Sub in seltzer water, sub out soda.

Substitution is also the principle for an exciting new area of research called therapeutic plasma exchange (TPE), the replacement of part of a patient’s blood plasma with a substitute. TPE is used to treat a large and growing number of immunologic, neurologic, connective tissue, hematologic, nephrologic, endocrinologic and metabolic disorders. Though clinical trials of plasma exchange for rare disorders are extremely difficult and costly, a growing body of evidence supporting individual indications is available, such as for steroid resistant optic deficits in multiple sclerosis and autoimmune encephalitis. Now more data is accumulating that TPE can help you reboot to preserve brain functioning and to make you live younger longer.

And it really has a chance to improve function, not just protect. The evidence of benefit of TPE in this AMBAR study in the mild AD patients is even more exciting because patients demonstrated improvements, not just reduced deterioration, compared to the placebo group. Those improvements persisted for the entire fifteen months of study. This indicates that TPE might effectively prevent AD if AD is not fully developed.

It has potential with immune disorders. TPE therapy has demonstrated preclinical or clinical benefits in a number of disorders associated with autoimmunity.

Why It Matters: TPE has implications in aging and longevity. This form of senolysis –getting rid of old stuff in the plasma--is an active area of investigation (as are all 14 areas of aging mechanism research)--to decrease rate of aging or to reboot to a cognitive level of a younger person –it is moving beyond animal studies to humans—the Conboys’ animal studies show regeneration of all tissues examined. Early human data from Kiprov and the Buck institute indicate the same for humans.

Update 5 1 25 TPE The data from Kiprov and the Buck on TPE and aging (and from the originators of its effects The Conboys) are now in early publication form (doi.org/10.110/2024.08.02.24310303) for us to examine; the data look substantial enough that I expect to start with 2 treatments in June and another 2 in July and then maybe 2 more in August and then yearly, and to start a clinic with others….it just isn’t that available.

The mechanism of action of Therapeutic Plama Exchange—getting rid of stuff –whether making the body produce new proteins or getting rid of contaminants that make proteins dysfunctional –isn’t clear, but the data from animals and now humans with and without cognitive dysfunction resulting in a younger aging biology (and biomarkers) and a recovery from early cognitive dysfunction is impressive enough to experience it myself.

Update 5 1 25 Senorejuvenators: Data from a Chinese study ((Bi et al., 2025, Cell Metabolism 37, 1–15 February 4, 2025 ª Authors Youkun Bi, Xinlong Qiao, Zhaokui Cai, ..., https://doi.org/10.1016/j.cmet.2024.11.013.) indicated not just senolysis but senorejuvenation of old cells into young cells with life and functional extension in mice.

Why It Matters:How far away can larger animal studies and human studies be? If you can increase stem cell production so you can repair cells with specific telomerase generation (see an update on this area in a future Update here) and get rid of missignalling and dysfunctional proteins with TPE and rejuvenate senile cells, you may have a 90 is the new 40 soon.

The exponential progress in time and in understanding continues.

Thanks for reading,

Mike Roizen MD