Therapeutic Approaches for Age-Related Diseases

An important longevity development is too-little discussed in the field for years: Despite many Aβ trial failures (& little benefit of the few successes), there's another misfolded protein possibly as important in aging with much success: ATTR now has 5 FDA approved therapies! TTR is an important protein but ATTR (transthyretin amyloidosis) is a pathological misfolded aggregate involved in many age-related conditions, notably cardiomyopathy (ATTR-CM), but also neuropathies & other age-related conditions (see pic). Importantly, it's widely quoted in scientific literature that ATTR is the primary cause of death of 70% of supercentenarians (age 110+). https://lnkd.in/gunmECuX Most of the rest die of aspiration pneumonia. So effective ATTR tx should extend human lifespans, maybe past 120. There's growing evidence ATTR is involved in cardiac deaths at lower ages too. It's found in 25% of 85+yos on autopsy & ~15% of those considered for valve replacement on scan. https://lnkd.in/g9dq62uA It's widely speculated its underdiagnosed. So tx could lower cardiac deaths generally. What therapies? (all now listed at AgingBiotech.info / therapeutics) patisiran (approved 2018) inotersen ('18) tafamidis ('19) vutisiran ('22) acoramidis (just approved Nov'24) (& a 6th is in phase 3) From 4 different companies. 2 TTR stabilizer drugs. The rest suppress TTR production (by RNAi or ASO). Due to the underdiagnosis, we don't know how much disease burden of the many age-related conditions pic'ed above (eg muscle weakness) is due to ATTR. Non-invasive scans can dx, but expensive. Amprion's seed amplification tech could make a widespread screening blood test w/ a bit of investment $. Important to note that all approved tx so far are not rejuvenative: They slow progression by slowing TTR production or TTR misfolding but don't remove already accumulated ATTR. But Attralus is in phase 2 w/ a removal tx (also w/ a dx). We will need removal eventually so good luck to them! So: Proteostasis is a aging hallmark, SENS area, & pillar. This is a key misfolding protein. It controls mortality of the oldest humans. We have phase-3-clinical-trial-proven FDA-approved therapies & potential diagnostics. We could already be on the way to 120+yo humans. Why is this not talked about more? Let's contrast this topic vs 2 of the most talked about topics in aging/longevity field, GLP-1 drugs & Bryan Johnson: GLP-1 drugs slow aging in overweight/obesity (really they rescue the sped up aging). Bryan's extreme lifestyle optimization tries to optimize longevity w/ everything available. Few in the aging field think Bryan's routine extends his max lifespan much. It improves healthspan so may let him live to see new breakthrus. Few thinks GLP1 drugs help humans exceed 120. ATTR therapies may help everyone 70/80/90yo+ *and* look likely to extend maximum human lifespan.

Aging and disease accelerate when lysosomes fail, and slow down when we fix them. This is an underappreciated, shared mechanism contributing to everything from cellular senescence and #inflammaging to mitochondrial dysfunction and Parkinson's disease. Every cell generates waste—damaged proteins, oxidized lipids, and mitochondria that have exceeded their useful lifespan. Lysosomes recycle this cellular debris, while also coordinating key signaling events that tell cells which nutrients are available and which ones are scarce. But over time, this system breaks down. Lysosomes become swollen, sluggish, and leaky. They stop degrading waste efficiently. Damaged materials pile up—especially in senescent cells, where dysfunctional lysosomes accumulate in bulk. Instead of recycling cellular waste, they start to trigger inflammation and fuel the #aging process. It’s not just passive decline. Lysosomal failure actively drives aging hallmarks like the accumulation of misfolded proteins, mitochondrial dysfunction, senescence and the SASP, chronic inflammation, and deregulated nutrient sensing. Thankfully, lysosomal dysfunction is also highly druggable. In fact, many of the most promising longevity interventions already converge on the lysosome, often by enhancing what’s been called the "lysosomal processing and adaptation system," or LYPAS: • Rapamycin inhibits mTORC1 at the lysosomal surface, releasing the brake on autophagy and activating TFEB—the transcription factor that builds new lysosomes. • Metformin, once thought to target mitochondrial complex I, actually binds to PEN2, a lysosomal membrane protein, and activates AMPK (which is also anchored at the lysosome). • Acarbose and SGLT2 inhibitors mimic caloric restriction, indirectly reducing mTORC1 activity and restoring lysosomal flux. • Compounds like spermidine, trehalose, and lithium each enhance autophagy by stimulating lysosomal turnover or TFEB signaling. • Even 17α-estradiol, in male mice, downregulates growth signaling pathways that suppress lysosomal renewal. These compounds work in part by replacing old, dysfunctional lysosomes with new, functional ones. But many of the best compounds for boosting lysosomal health haven't even been tested for #longevity and #healthspan indications. As this connection gathers more attention, I suspect we'll see breakthroughs here—targeted therapies that preserve lysosomal function throughout the lifespan, preventing decline and disrupting the cascade of aging-related damage. A recent review from Tan & Finkel provides an excellent summary. Link in the comments.

Just wanted to share a great weekend read about ways to fight cardiovascular aging ♥️ 📑 This new article in Nature Reviews Cardiology by Liberale et al. (2025) provides a comprehensive roadmap for tackling cardiovascular aging, not just by managing risk factors, but by targeting the biological mechanisms of aging itself. The circulatory system is a master regulator of health, and its decline accelerates dysfunction across multiple organs. 👇 Below are some high level insights from the study: ✔ Cardiovascular aging is not just ‘wear and tear.’ Ageing causes fundamental changes at the molecular and cellular levels: endothelial dysfunction, mitochondrial failure, immune dysregulation, and extracellular matrix remodeling. This affects every level of the cardiovascular system, from large arteries to capillaries, from blood cells to cardiac tissue. ✔ Aging is driven by hallmarks like senescence and epigenetic reprogramming The study outlines 12 hallmarks of ageing that contribute to cardiovascular dysfunction, including telomere attrition, mitochondrial dysfunction, chronic inflammation, and impaired autophagy. Cellular senescence plays a major role—senescent endothelial cells trigger arterial stiffening, inflammation, and thrombosis. ✔ Ageing biomarkers could revolutionize preventive medicine Current risk assessment (e.g., cholesterol, blood pressure) may be insufficient in older adults. Instead, tracking biological ageing through single-cell omics, DNA methylation clocks, and inflammatory markers could allow earlier interventions. Future clinical trials should prioritize biological age markers, not just cardiovascular disease endpoints. 💊 Beyond lifestyle, the growing hope for gerotherapeutics: ✔️ The article highlights senolytics (to clear aged cells), metformin (to modulate metabolism), and rapamycin (to slow ageing pathways) as promising strategies. ✔️ More targeted therapies (e.g., mitochondrial enhancers, epigenetic reprogramming) are under investigation. ✔️ Immunomodulation: Tackling age-related immune dysfunction could reduce inflammageing and cardiovascular risk. Kudos to authors, including David Furman from Buck Institute for Research on Aging! Image credit: Nature Reviews Cardiology

For nearly 30 years, we've had exactly one class of drugs for Alzheimer's: acetylcholinesterase inhibitors. While helpful, donepezil and its siblings never changed the disease course - they just managed symptoms. Meanwhile, the amyloid hypothesis devoured $30+ billion. Despite skepticism peaking in 2010-2016 after repeated failures, pharma doubled down. By 2019, over 200 trials targeting amyloid had failed to improve patient cognition or function. Yet another $20+ billion followed. Why this costly persistence? ↳ FDA's controversial aducanumab approval sent the wrong signal ↳ Decades of sunk costs made pivoting away too painful ↳ Biomarker improvements (amyloid PET scans) replaced meaningful outcomes ↳ The same failed hypothesis kept getting repackaged This approach prioritized measurable lab values over patient experience, ultimately eroding trust in pharmaceutical research, regulatory oversight, and the scientific process itself. Thankfully, real progress is happening elsewhere. These 5 therapies show actual cognitive and functional improvements: 1/ 40Hz Light & Sound Therapy ↳ Restores gamma brain oscillations disrupted in Alzheimer's ↳ Shows 72% less whole-brain atrophy at 6 months vs. placebo ↳ 83% less cognitive decline on MMSE in Phase 2 trials ↳ Non-invasive with no serious side effects—can be used at home 2/ Blarcamesine (Anavex 2-73) ↳ Oral drug activating sigma-1 receptors to enhance cellular resilience ↳ Slowed decline by 30-35% in cognition and daily function ↳ ~37% less brain atrophy on MRI scans ↳ Well-tolerated with no brain swelling or bleeding risks 3/ Laromestrocel (Lomecel-B) ↳ Intravenous stem cell therapy with regenerative potential ↳ 48% less whole-brain atrophy and 62% less hippocampal volume loss ↳ Improved neuroinflammation markers in Phase 2a trial ↳ No brain swelling side effects that plague antibody treatments 4/ Simufilam ↳ Oral drug stabilizing filamin A to restore receptor signaling ↳ Patients actually improved cognition over 12 months ↳ Average cognitive scores increased from baseline (not just slowed decline) ↳ Phase 3 trials will provide definitive evidence 5/ Neflamapimod ↳ Targets neuroinflammation through p38 MAPK inhibition ↳ First therapy showing improvement in Lewy Body Dementia ↳ Significant cognitive and functional gains after dose optimization ↳ Also reduced falls and improved quality of life These treatments work through diverse mechanisms, not just targeting amyloid plaques. Success will come when we prioritize patient outcomes over biomarkers, and functional improvement over theoretical models. —----------------------------- ⁉️ Comment below: How do we rebuild trust in dementia research after decades of misplaced focus? ♻️ Share to spread hope to families affected by dementia. 👉 Follow me (Reza Hosseini Ghomi, MD, MSE) for more like this.

TARGETING BRAIN'S DRAINAGE PATHWAYS REJUVENATES MEMORY Rejuvenating the brain’s lymphatic vessels can enhance memory in aging mice by improving the removal of waste products from the brain. This research suggests that targeting the meningeal lymphatics—vessels outside the brain—could be a novel approach to treating age-related cognitive decline without directly crossing the blood-brain barrier. The treatment reduced levels of the inflammatory protein IL-6 and restored healthy neuronal signaling, alleviating memory loss in older mice. These findings open the door to therapies that enhance brain function by supporting the body’s natural “waste management” system. 3 Key Facts: 1. Waste Clearance Pathway: Enhancing meningeal lymphatic drainage improved memory in aged mice. 2. Inflammatory Link: Treatment reduced IL-6 levels, restoring healthy brain communication. 3. Therapeutic Potential: Targeting lymphatic vessels outside the brain could offer non-invasive options for age-related cognitive decline. Source: https://lnkd.in/gYUr6sxA